U.S. patent application number 13/513667 was filed with the patent office on 2012-11-01 for benzamide compound.
This patent application is currently assigned to ASTELLAS PHARMA INC.. Invention is credited to Masahiko Hayakawa, Takanori Koike, Keisuke Maki, Takahiro Nigawara, Mitsuaki Okumura, Daisuke Sasuga, Seiji Yoshimura.
Application Number | 20120277208 13/513667 |
Document ID | / |
Family ID | 44145640 |
Filed Date | 2012-11-01 |
United States Patent
Application |
20120277208 |
Kind Code |
A1 |
Hayakawa; Masahiko ; et
al. |
November 1, 2012 |
BENZAMIDE COMPOUND
Abstract
[Problem]A compound which is useful as a GK activator is
provided. [Means for Solution] The present inventors have conducted
studies on compounds having a GK activating action, which are
promising as active ingredients of pharmaceutical compositions for
the treatment of diabetes, type 2 diabetes mellitus, obesity,
metabolic syndrome and related diseases caused by the
aforementioned diseases, and as a result, they have confirmed that
a benzamide compound of the present invention has an excellent GK
activating action, thereby completing the present invention. That
is, the benzamide compound of the present invention has a GK
activating action and can be used as an agent for preventing and/or
treating diabetes, type 2 diabetes mellitus, obesity, metabolic
syndrome, and related diseases caused by the aforementioned
diseases.
Inventors: |
Hayakawa; Masahiko; (Tokyo,
JP) ; Yoshimura; Seiji; (Tokyo, JP) ; Sasuga;
Daisuke; (Tokyo, JP) ; Koike; Takanori;
(Tokyo, JP) ; Nigawara; Takahiro; (Tokyo, JP)
; Okumura; Mitsuaki; (Tokyo, JP) ; Maki;
Keisuke; (Tokyo, JP) |
Assignee: |
ASTELLAS PHARMA INC.
Chuo-ku, Tokyo
JP
|
Family ID: |
44145640 |
Appl. No.: |
13/513667 |
Filed: |
December 9, 2010 |
PCT Filed: |
December 9, 2010 |
PCT NO: |
PCT/JP2010/072077 |
371 Date: |
June 4, 2012 |
Current U.S.
Class: |
514/210.18 ;
514/236.2; 514/252.11; 514/255.05; 514/255.06; 514/341; 514/407;
544/131; 544/295; 544/336; 544/357; 544/405; 546/269.4;
548/365.7 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
403/14 20130101; C07D 285/08 20130101; C07D 401/14 20130101; A61P
3/06 20180101; A61P 9/00 20180101; A61P 9/08 20180101; A61P 27/02
20180101; C07D 403/12 20130101; C07D 409/14 20130101; A61P 13/12
20180101; C07D 241/20 20130101; C07D 413/12 20130101; A61P 3/00
20180101; C07D 213/80 20130101; C07D 231/40 20130101; A61P 25/00
20180101; C07D 213/75 20130101; C07D 277/46 20130101; C07D 277/20
20130101; C07D 413/14 20130101; C07D 405/14 20130101; A61P 3/04
20180101; A61P 3/10 20180101; C07D 405/12 20130101; A61P 43/00
20180101 |
Class at
Publication: |
514/210.18 ;
544/405; 514/255.05; 544/336; 514/255.06; 546/269.4; 514/341;
544/131; 514/236.2; 548/365.7; 514/407; 544/295; 544/357;
514/252.11 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61P 3/04 20060101 A61P003/04; A61P 3/10 20060101
A61P003/10; C07D 241/20 20060101 C07D241/20; A61K 31/4965 20060101
A61K031/4965; C07D 413/14 20060101 C07D413/14; A61K 31/4439
20060101 A61K031/4439; C07D 405/14 20060101 C07D405/14; A61K
31/5377 20060101 A61K031/5377; C07D 405/12 20060101 C07D405/12;
A61K 31/4155 20060101 A61K031/4155; C07D 403/14 20060101
C07D403/14; A61K 31/506 20060101 A61K031/506; C07D 409/14 20060101
C07D409/14; C07D 403/12 20060101 C07D403/12 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 11, 2009 |
JP |
2009-281350 |
Claims
1. A compound of the formula (I) or a salt thereof. ##STR00374##
[the symbols in the formula have the following meanings: Ring A:
nitrogen-containing heteroaryl which may be substituted, X.sup.1
and X.sup.2: the same as or different from each other, each
representing C(H), C(R.sup.2), or N, R.sup.1: --N(halogeno-lower
alkyl)-C(O)--R.sup.11, --N(lower
alkylene-cycloalkyl)-C(O)--R.sup.11, --N(lower
alkylene-cycloalkyl)-CO.sub.2R.sup.11,
--N(lower)alkylene-cycloalkyl)-C(O)N(R.sup.0)(R.sup.11), --N(lower
alkylene-cycloalkyl)-S(O).sub.2--R.sup.11, or R.sup.12, R.sup.0:
the same as or different from each other, each representing --H, or
lower alkyl, R.sup.11: lower alkyl, halogeno-lower alkyl, lower
alkylene-OR.sup.0, lower alkylene-O-lower alkylene-OR.sup.0, lower
alkylene-OC(O)-lower alkyl, lower alkylene-CN, lower)
alkylene-N(R.sup.0).sub.2, lower alkylene-cycloalkyl, cycloalkyl,
or a heterocyclic group, provided that the cycloalkyl and the
heterocyclic group in R.sup.11 may be each substituted, R.sup.12:
2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or 1,3,4-oxadiazol-2-yl,
each of which may be substituted with a group selected from Group
G, provided that when both of X.sup.1 and X.sup.2 are not N,
1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl in R.sup.12 are
substituted with a group selected from Group G, Group G: lower
alkylene-CN, lower alkylene-OR.sup.0,
lower)alkylene-N(R.sup.0).sub.2, lower
alkylene-C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0).sub.2,
--C(O)N(R.sup.0)-lower alkylene-OR.sup.0,
--C(O)N(R.sup.0)-cycloalkyl, --C(O)N(R.sup.0)-heterocyclic group,
--C(O)-heterocyclic group, --N(R.sup.0).sub.2, --S(O).sub.p-lower
alkyl, and cycloalkyl, provided that the cycloalkyl and the
heterocyclic group in Group G may be substituted, R.sup.2: the same
as or different from each other, each representing halogen, lower
alkyl, --O-lower alkyl, or --O-halogeno-lower alkyl, n and p: the
same as or different from each other, each representing 0, 1, or 2,
R.sup.3: --H, halogen, lower alkyl, halogeno-lower alkyl,
--N(R.sup.0)C(O)-lower alkyl, --N(lower
alkylene-cycloalkyl)-C(O)-lower alkyl, or --O--R.sup.31, and
R.sup.31: --H, lower alkyl, halogeno-lower alkyl, lower
alkylene-OR.sup.0, lower alkylene-N(R.sup.0).sub.2, lower
alkylene-S(O).sub.2-lower alkyl,
lower)alkylene-C(O)N(R.sup.0)--S(O).sub.2-lower alkyl, lower
alkylene-cycloalkyl, lower alkylene-aryl, cycloalkyl, or
heterocyclic group, provided that the cycloalkyl, aryl, and
heterocyclic groups in R.sup.31 may be each substituted].
2. The compound according to claim 1, wherein R.sup.1 is --N(lower
alkylene-cycloalkyl)-C(O)--R.sup.11 or R.sup.12.
3. The compound according to claim 2, wherein Ring A is
pyrazol-3-yl, thiazol-2-yl or 1,2,4-thiadiazol-5-yl, each of which
may be substituted with lower alkyl which may be substituted with a
hydroxyl group.
4. The compound according to claim 3, wherein R.sup.3 is --O-lower
alkyl, --O-halogeno-lower alkyl, --O-lower alkylene-OR.sup.0,
--O-(cycloalkyl which may be substituted with
lower)alkylene-OR.sup.0, --O-lower alkylene-aryl, or --N(lower
alkylene-cycloalkyl)-C(O)-lower alkyl.
5. The compound according to claim 4, wherein X.sup.1 is C(H) and
X.sup.2 is N or wherein X.sup.1 is N and X.sup.2 is N.
6. The compound according to claim 5, wherein n is 0.
7. The compound according to claim 6, wherein R.sup.1 is
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, each of which is substituted with a group
selected from the group consisting of lower alkylene-OR.sup.0,
--C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0)-lower alkylene-OR.sup.0,
and --C(O)N(R.sup.0)-cycloalkyl.
8. The compound according to claim 6, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)-lower alkylene-O-lower
alkylene-OR.sup.0,
--N(cyclopropylmethyl)-C(O)-lower)alkylene-N(R.sup.0).sub.2, or
-N(cyclopropylmethyl)-C(O)--(heterocyclic group which may be
substituted with a group selected from the group consisting of
lower alkyl, halogeno-lower alkyl, --O--R.sup.0, --O-halogeno-lower
alkyl, and oxo).
9. The compound or a salt thereof according to claim 1, which is
selected from the group consisting of:
3-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazin-
-2-yl)-N,N-dimethyl-1,2,4-oxadiazole-5-carboxamide,
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)-2-oxoimidazolidine-1-carboxamide,
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)pyrazine-2-carboxamide,
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazin-
-2-yl)-N,N-dimethyl-1,3,4-oxadiazole-2-carboxamide,
3-[(5-{(cyclopropylmethyl)[(2-methoxyethoxy)acetyl]amino}pyrazin-2-yl)oxy-
]-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,
(2R)-N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-y-
l)carbamoyl]phenoxy}pyrazin-2-yl)tetrahydrofuran-2-carboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-N,N-dimethyl-1,2,4-oxadiazole-3-carboxamide,
N-(5-{3-[acetyl(cyclopropylmethyl)amino]-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-ca-
rboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]pheno-
xy}pyridin-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide,
N-(2-hydroxyethyl)-5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbam-
oyl]phenoxy}pyridin-2-yl)-1,2,4-oxadiazole-3-carboxamide,
3-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-N,N-dimethyl-1,2,4-oxadiazole-5-carboxamide,
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazin-
-2-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide,
N-(cyclopropylmethyl)-N-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-5-[(1-meth-
yl-1H-pyrazol-3-yl)carbamoyl]phenoxy)pyrazin-2-yl]tetrahydro-2H-pyran-4-ca-
rboxamide,
5-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazo-
l-3-yl)carbamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxamide,
5-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxamide,
3-[(5-{(cyclopropylmethyl)[(2-methoxyethoxy)acetyl]amino}pyrazin-2-yl)oxy-
]-5-{[(2S)-1-hydroxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide-
,
Description
TECHNICAL FIELD
[0001] The present invention relates to a benzamide compound which
is useful as an active ingredient of a pharmaceutical composition,
for example, a pharmaceutical composition for treating
diabetes.
BACKGROUND ART
[0002] GK (glucokinase (ATP: D-hexose 6-phosphotransferase,
EC2.7.1.1)) is an enzyme which is expressed in the pancreas and the
liver and phosphorylates hexose, and its presence in the brain has
also been revealed in recent years. This enzyme belongs to a
hexokinase family and is also called hexokinase IV as an alias. As
compared with other hexokinases, GK has characteristics such as 1)
it has low affinity for glucose as its substrate and shows a Km
value close to the blood glucose concentration, 2) it is not
inhibited by glucose-6-phosphate which is its enzyme reaction
product, 3) it has a molecular weight of 50 kDa which is about half
of those of other hexokinases, and the like. The human glucokinase
gene is positioned at the 7.sup.th chromosome 7p13 as a single gene
and controlled by 30 kb or more distant tissue-specific different
promoters in pancreatic .beta. cells and hepatic cells and uses a
different first exon but the other exons 2 to 10 are common.
Accordingly, between the pancreatic and hepatic GK proteins, only
the N-terminal 15 residues are different.
[0003] Accompanied by an increase in the blood glucose level, the
glucose concentration in the pancreatic .beta. cells quickly
reaches its equilibrium via a glucose transporting carrier GLUT 2,
and GK detects a change in the intracellular glucose concentration
and activates the glycolytic system. As a result, the ATP/ADP ratio
in the pancreatic .beta. cells increases and the KATP channel is
closed, and a voltage-dependent Ca channel detects this and the
intracellular calcium concentration is thereby increased and
release of insulin occurs. That is, GK acts as a glucose sensor in
the pancreatic .beta. cells and plays an important role in the
control of insulin secretion. GK also acts as a glucose sensor in
the liver, responds to the increase in the blood glucose level and
converts glucose into glucose-6-phosphate. As a result, production
of glycogen increases, and the glycolytic system is also activated
and the gluconeogenesis in the liver is thereby inhibited.
[0004] In patients whose glucose phosphorylation ability has been
reduced due to gene mutation of GK, hyperglycemia occurs
frequently, and juvenile diabetes is generated (MODY 2). On the
other hand, in patients who show a low value of the Km value of GK
activity due to a gene mutation, hypoglycemia is recognized after
meals and at the time of fasting. That is, GK also acts as a
glucose sensor in humans and thereby plays an important role in
maintaining normal blood glucose levels. From these facts, it is
expected that an agent capable of activating GK will become an
excellent agent for treating type 2 diabetes mellitus, which
corrects hyperglycemia after meals by accelerating
glucose-dependent insulin secretion from the pancreatic .beta.
cells, and at the same time, inhibits release of glucose from the
liver. Further, there also is a possibility that excess
acceleration of insulin secretion does not occur due to
acceleration of glucose uptake into the liver under a hyperglycemic
state after meals, and therefore that the pancreatic secondary
failure as a conventional problem with sulfonylurea (SU) agents can
be avoided. In addition, it has been reported in recent years that
apoptosis is induced when a mouse cultured pancreatic cell (MIN6N8)
is cultured under high glucose conditions. In addition, since
apoptosis of the MIN6N8 was inhibited when glucokinase was
over-expressed in this cell (Diabetes 54:2) 2602-2611 (2005)), it
is expected that a GK activating agent will show a pancreas
protective action.
[0005] The GK which exists in the brain is a pancreas type and
frequently expressed in the nerve of a feeding center VMH
(ventromedial hypothalamus). Glucose-sensitive nerves are
classified into GE (Glucose Exited)-neurons, which is excitatory
for glucose and GI (Glucose Inhibited)-neurons, which is
suppressive for glucose. The presence of mRNA and protein of GK is
found in about 70% of the GE-neurons and about 40% of the
GI-neurons.
[0006] In these glucose-sensitive nerves, GK detects increase of
the intracellular glucose and activates the glycolytic system, and
thus, the intracellular ATP/ADP ratio increases. As a result, the
KATP channel is closed in the GE-neuron, frequency of action
potential of the neuron is increased and a neurotransmitter is
released. On the other hand, it is considered that a C1-channel is
involved in the GI-neuron. In a rat in which expression of GK mRNA
is increased in the VMH, a compensatory action for the
glucose-deficient state is reduced.
[0007] Receptors for leptin and insulin involved in the feeding
behavior are also present in the glucose-sensitive nerves. In the
GE-neuron under a high glucose condition, leptin and insulin open
the KATP channel and reduce the frequency of action potential. In
addition, the NPY (Neuropeptide Y)-neuron which functions to
promote appetite at the ARC (arcuate nucleus) is suppressive for
glucose and the POMC (Proopiomelanocortin)-neuron which functions
to suppress appetite is excitatory for glucose (Diabetes
53:2521-2528 (2004)). From these facts, suppression of feeding
behavior is expected by activating GK of the central nervous
system, which is effective for the treatment of obesity or
metabolic syndrome.
[0008] A large number of compounds having the GK activation action
have been reported, and there is also report of a compound whose
clinical efficacy has been confirmed. However, a novel GK activator
having an excellent profile regarding reduction in various side
effects (actions for hERG or CYP) or solubility is in great
demand.
[0009] Benzamide derivatives having a GK activation action have
been reported in Patent Documents 1 to 22, but there is no specific
disclosure of the compound of the present invention.
[0010] [Patent Document 1] Pamphlet of International Publication WO
2009/041475
[0011] [Patent Document 2] Pamphlet of International Publication WO
2004/076420
[0012] [Patent Document 3] Pamphlet of International Publication WO
2008/075073
[0013] [Patent Document 4] Pamphlet of International Publication WO
2008/050117
[0014] [Patent Document 5] Pamphlet of International Publication WO
2008/050101
[0015] [Patent Document 6] Pamphlet of International Publication WO
2007/060448
[0016] [Patent Document 7] Pamphlet of International Publication WO
2007/017649
[0017] [Patent Document 8] Pamphlet of International Publication WO
2007/007042
[0018] [Patent Document 9] Pamphlet of International Publication WO
2007/007040
[0019] [Patent Document 10] Pamphlet of International Publication
WO 2006/040529
[0020] [Patent Document 11] Pamphlet of International Publication
WO 2006/040528
[0021] [Patent Document 12] Pamphlet of International Publication
WO 2006/040527
[0022] [Patent Document 13] Pamphlet of International Publication
WO 2005/121110
[0023] [Patent Document 14] Pamphlet of International Publication
WO 2005/080360
[0024] [Patent Document 15] Pamphlet of International Publication
WO 2005/080359
[0025] [Patent Document 16] Pamphlet of International Publication
WO 2005/056530
[0026] [Patent Document 17] Pamphlet of International Publication
WO 2005/054233
[0027] [Patent Document 18] Pamphlet of International Publication
WO 2005/054200
[0028] [Patent Document 19] Pamphlet of International Publication
WO 2005/044801
[0029] [Patent Document 20] Pamphlet of International Publication
WO 2003/015744
[0030] [Patent Document 21] Pamphlet of International Publication
WO 2007/007041
[0031] [Patent Document 22] Pamphlet of International Publication
WO 2010/092387
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
[0032] A benzamide compound which is useful as an active ingredient
of a pharmaceutical composition, for example, a pharmaceutical
composition for treating diabetes, is provided.
Means for Solving the Problems
[0033] The present inventors have made extensive studies on
compounds having a GK activating action, and as a result, they have
found that the benzamide compound of the present invention has a GK
activating action, thereby completing the present invention.
[0034] That is, the present invention relates to a compound of the
formula (I) or a salt thereof as well as a pharmaceutical
composition containing a compound of the formula (I) or a salt
thereof and pharmaceutically acceptable excipients.
##STR00001##
[0035] [the symbols in the formula have the following meanings:
[0036] Ring A: nitrogen-containing heteroaryl which may be
substituted,
[0037] X.sup.1 and X.sup.2: the same as or different from each
other, each representing C(H), C(R.sup.2), or N,
[0038] R.sup.1: --N(halogeno-lower alkyl)-C(O)--R.sup.11, --N(lower
alkylene-cycloalkyl)-C(O)--R.sup.11, --N(lower
alkylene-cycloalkyl)-CO.sub.2R.sup.11,
--N(lower)alkylene-cycloalkyl)-C(O)N(R.sup.0)(R.sup.11 ), --N(lower
alkylene-cycloalkyl)-S(O).sub.2--R.sup.11, or R.sup.12,
[0039] R.sup.0: the same as or different from each other, each
representing --H, or lower alkyl,
[0040] R.sup.11: lower alkyl, halogeno-lower alkyl, lower
alkylene-OR.sup.0, lower alkylene-O-lower alkylene-OR.sup.0, lower
alkylene-OC(O)-lower alkyl, lower alkylene-CN, lower)
alkylene-N(R.sup.0).sub.2, lower alkylene-cycloalkyl, cycloalkyl,
or a heterocyclic group,
[0041] provided that the cycloalkyl and the heterocyclic group in
R.sup.11 may be each substituted,
[0042] R.sup.12: 2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, each of which may be substituted with a group
selected from Group G,
[0043] provided that when both of X.sup.1 and X.sup.2 are not N,
1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl in R.sup.12 are
substituted with a group selected from Group G,
[0044] Group G: lower alkylene-CN, lower alkylene-OR.sup.0,
lower)alkylene-N(R.sup.0).sub.2, lower
alkylene-C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0).sub.2,
--C(O)N(R.sup.0)-lower alkylene-OR.sup.0,
--C(O)N(R.sup.0)-cycloalkyl, --C(O)N(R.sup.0)-heterocyclic group,
--C(O)-heterocyclic group, --N(R.sup.0).sub.2, --S(O).sub.p-lower
alkyl, and cycloalkyl,
[0045] provided that the cycloalkyl and the heterocyclic group in
Group G may be substituted,
[0046] R.sup.2: the same as or different from each other, each
representing halogen, lower alkyl, --O-lower alkyl, or
--O-halogeno-lower alkyl,
[0047] n and p: the same as or different from each other, each
representing 0, 1, or 2,
[0048] R.sup.3: --H, halogen, lower alkyl, halogeno-lower alkyl,
--N(R.sup.0)C(O)-lower alkyl, --N(lower
alkylene-cycloalkyl)-C(O)-lower alkyl, or --O--R.sup.31, and
[0049] R.sup.31: --H, lower alkyl, halogeno-lower alkyl, lower
alkylene-OR.sup.0, lower alkylene-N(R.sup.0).sub.2, lower
alkylene-S(O).sub.2-lower alkyl,
lower)alkylene-C(O)N(R.sup.0)--S(O).sub.2-lower alkyl, lower
alkylene-cycloalkyl, lower alkylene-aryl, cycloalkyl, or
heterocyclic group,
[0050] provided that the cycloalkyl, aryl, and heterocyclic groups
in R.sup.31 may be each substituted].
[0051] Moreover, unless specified otherwise, in the case where the
symbols of the chemical formulae in the present specification are
also used in other chemical formulae, the same symbols denote the
same meanings.
[0052] Furthermore, the present invention relates to a GK activator
containing a compound of the formula (I) or a salt thereof.
Further, in another embodiment, the present invention relates to a
pharmaceutical composition for preventing and/or treating diabetes,
type 2 diabetes mellitus, obesity, or metabolic syndrome, which
contains a compound of the formula (I) or a salt thereof. In
addition, the pharmaceutical composition includes an agent for
preventing and/or treating diabetes, type 2 diabetes mellitus,
obesity, or metabolic syndrome, which contains a compound of the
formula (I) or a salt thereof.
[0053] Furthermore, the present invention relates to use of a
compound of the formula (I) or a salt thereof for preparation of a
GK activator, or a pharmaceutical composition for preventing or
treating diabetes, type 2 diabetes mellitus, obesity, or metabolic
syndrome, a compound of the formula (I) or a salt thereof to be
used for preventing or treating diabetes, type 2 diabetes mellitus,
obesity, or metabolic syndrome, and a method for preventing and/or
treating diabetes, type 2 diabetes mellitus, obesity, or metabolic
syndrome including administering an effective amount of a compound
of the formula (I) or a salt thereof to a subject. Further, the
"subject" is a human or another animal in need of such prevention
or treatment, and in a certain embodiment, a human in need of such
prevention or treatment.
[0054] That is, the present invention also relates to
[0055] (1) a pharmaceutical composition comprising a compound of
the formula (I) or a salt thereof and pharmaceutically acceptable
excipients;
[0056] (2) the pharmaceutical composition according to (1), which
is a GK activator;
[0057] (3) the pharmaceutical composition according to (1), which
is a drug for preventing and/or treating diabetes;
[0058] (4) the pharmaceutical composition according to (3), which
is a drug for preventing and/or treating type 2 diabetes
mellitus;
[0059] (5) the pharmaceutical composition according to (1), which
is a drug for preventing and/or treating obesity;
[0060] (6) the pharmaceutical composition according to (1), which
is a drug for preventing and/or treating metabolic syndrome;
[0061] (7) use of a compound of the formula (I) or a
pharmaceutically acceptable salt thereof for the preparation of a
GK activator, or a drug for preventing and/or treating diabetes,
obesity, or metabolic syndrome;
[0062] (8) use of a compound of the formula (I) or a
pharmaceutically acceptable salt thereof for preventing and/or
treating diabetes, obesity, or metabolic syndrome;
[0063] (9) a method for preventing and/or treating diabetes,
obesity, or metabolic syndrome, comprising administering to a
patient a therapeutically effective amount of a compound of the
formula (I) or a salt thereof;
[0064] (10) a compound of the formula (I) or a pharmaceutically
acceptable salt thereof for preventing and/or treating diabetes,
obesity, or metabolic syndrome.
EFFECTS OF THE INVENTION
[0065] A compound of the formula (I) or a salt thereof has a GK
activating action, and can be used as an active ingredient of a
pharmaceutical composition for preventing and/or treating diabetes,
particularly type 2 diabetes mellitus. Further, it can be used as
an active ingredient of a pharmaceutical composition for preventing
and/or treating nephropathy, retinopathy, neuropathy, peripheral
circulatory disorder, cerebrovascular disorder, ischemic heart
disease, and arteriosclerosis that are complications of diabetes
mellitus. It can further be used as an active ingredient of a
pharmaceutical composition for preventing and/or treating obesity
or metabolic syndrome by suppressing overeating.
Embodiments for Carrying Out the Invention
[0066] Hereinafter, the present invention will be described in
detail.
[0067] In the present specification, the "lower alkyl" preferably
refers to linear or branched alkyl having 1 to 6 carbon atoms
(hereinafter simply referred to as C.sub.1-6), specifically methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, n-hexyl, or the like, more preferably
C.sub.1-4 alkyl, and particularly preferably methyl, ethyl, normal
propyl, isopropyl, or tert-butyl.
[0068] The "lower alkylene" preferably refers to linear or branched
C.sub.1-6 alkylene, specifically, methylene, ethylene,
trimethylene, tetramethylene, pentamethylene, hexamethylene,
propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, a
1,1,2,2-tetramethylethylene group, or the like, more preferably
C.sub.1-4 alkylene, and still more preferably methylene, ethylene,
or trimethylene.
[0069] The "halogen" means F, Cl, Br, or I.
[0070] The "halogeno-lower alkyl" refers to C.sub.1-6 alkyl
substituted with one or more halogen atoms, preferably a lower
alkyl substituted with 1 to 5 halogen atoms, and more preferably
fluoromethyl, difluoromethyl, or trifluoromethyl.
[0071] The "cycloalkyl" refers to a C.sub.3-10 saturated
hydrocarbon ring group, which may have a bridge. It is specifically
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, an adamantyl group, or the like, preferably C.sub.3-8
cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl,
or cyclohexyl, and still more preferably cyclopropyl.
[0072] The "aryl" refers a C.sub.6-14 monocyclic to tricyclic
aromatic hydrocarbon ring group, more preferably phenyl or
naphthyl, and still more preferably phenyl.
[0073] "Heteroaryl" group means a 5- to 15-membered, preferably 5-
to 10-membered, monocyclic to tricyclic aromatic heterocyclic group
containing 1 to 4 hetero atoms selected from oxygen, sulfur, and
nitrogen. Sulfur or nitrogen which is a ring atom may be oxidized
to form an oxide. Specific examples of the heteroaryl group include
pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl,
oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzofuryl, benzoxazolyl, benzothienyl,
benzothiazolyl, [1,3]thiazolo[5,4-b]pyridinyl, quinolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,
naphthylizinyl, carbazolyl, and the like, preferably a 5- to
6-membered monocyclic heteroaryl, and more preferably pyrazolyl,
thiazolyl, thiadiazolyl, pyridyl, and pyrazinyl.
[0074] The "nitrogen-containing heteroaryl" group means heteroaryl
having at least one nitrogen atom among the aforementioned
"heteroaryl". Specific examples thereof include pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl,
isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, [1,3]thiazolo[5,4-b]pyridinyl, quinolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl,
naphthylizinyl, carbazolyl, and the like, preferably a 5- to
6-membered monocyclic nitrogen-containing heteroaryl, and more
preferably pyrazolyl, thiazolyl, thiadiazolyl, pyridyl, and
pyrazinyl.
[0075] The "heterocyclic" group refers to a 3- to 15-membered,
preferably 5- to 10-membered, monocyclic to tricyclic heterocyclic
group containing 1 to 4 hetero atoms selected from oxygen, sulfur,
and nitrogen, which contains a saturated ring, an aromatic ring,
and a partially hydrogenated ring group thereof and may have a
bridge. Sulfur or nitrogen which is a ring atom may be oxidized to
form an oxide or a dioxide. Specific examples of the heterocyclic
group include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,
piperidinyl, piperazinyl, morpholinyl, azepanyl, diazepanyl,
tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, oxazolyl,
isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl,
thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl,
benzofuryl, benzoxazolyl, benzothienyl, benzothiazolyl,
[1,3]thiazolo[5,4-b]pyridinyl, quinolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, naphthylizinyl, carbazolyl,
indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,
methylenedioxyphenyl, an ethylenedioxyphenyl group, and the like,
preferably a 5- to 9-membered monocyclic to bicyclic heterocyclic
group, more preferably a 5- to 6-membered monocyclic heterocyclic
group, and still more preferably pyrazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl,
pyrazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl,
pyrrolidinyl, imidazolidinyl, and piperidinyl.
[0076] The expression "which may be substituted" represents "which
is not substituted" or "which is substituted with 1 to 5
substituents, which are the same as or different from each other".
Further, the expression "which is substituted" represents "which
has 1 to 5 substituents, which are the same as or different from
each other". If there are a plurality of substituents, the
substituents may be the same as or different from each other.
[0077] The substituent of the "nitrogen-containing heteroaryl"
which may be substituted in the ring A is preferably a group
selected from Group G.sup.1, more preferably lower alkyl which may
be substituted with a hydroxyl group, and still more preferably
lower alkyl.
[0078] Group G.sup.1: halogen, lower alkyl which may be substituted
with --OR.sup.0, halogeno-lower alkyl, --OR.sup.0,
--O-halogeno-lower alkyl, --CO.sub.2R.sup.0, or a heterocyclic
group,
[0079] provided that the heterocyclic group in the group G.sup.1
may be substituted with a group selected from the group consisting
of lower alkyl, halogeno-lower alkyl, --OR.sup.0,
--O-halogeno-lower alkyl, and oxo.
[0080] The substituent of the "cycloalkyl" and the "heterocyclic
group", each of which may be substituted, in R.sup.11 is preferably
a group selected from the group consisting of lower alkyl,
halogeno-lower alkyl, --OR.sup.0, --O-halogeno-lower alkyl, and
oxo.
[0081] The substituent of the "cycloalkyl" and the "heterocyclic
group", each of which may be substituted, in Group G is preferably
a group selected from the group consisting of lower alkyl,
halogeno-lower alkyl, --OR.sup.0, --O-halogeno-lower alkyl, and
oxo.
[0082] The substituent of the "cycloalkyl", "aryl", and the
"heterocyclic group", each of which may be substituted, in R.sup.31
is preferably a group selected from the group consisting of
halogen, lower alkyl, --OR.sup.0, --O-halogeno-lower alkyl, lower
alkylene-OR.sup.0, and lower alkylene-O-lower alkylene-aryl.
[0083] Certain embodiments of the compound of the formula (I) or a
salt thereof are shown below.
[0084] (1) The compound or a salt thereof, wherein Ring A is
pyrazol-3-yl, thiazol-2-yl, or 1,2,4-thiadiazol-5-yl, each of which
may be substituted with lower alkyl which may be substituted with a
hydroxyl group, in another embodiment, the compound or a salt
thereof, wherein Ring A is pyrazol-3-yl or 1-methylpyrazol-3-yl,
and in a still another embodiment, the compound or a salt thereof,
wherein Ring A is 1-methylpyrazol-3-yl.
[0085] (2) (2-1) The compound or a salt thereof, wherein R.sup.1 is
R.sup.12, in another embodiment, the compound or a salt thereof,
wherein R.sup.1 is 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, each of which is substituted with a group
selected from the group consisting of lower alkylene-OR.sup.0,
--C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0)-lower alkylene-OR.sup.0,
and --C(O)N(R.sup.0)-cycloalkyl, in a still another embodiment, the
compound or a salt thereof, wherein R.sup.1 is
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, which is substituted with carbamoyl which may
be substituted with one or two lower alkyl groups (in which the
lower alkyl may be substituted with a hydroxyl group), in a further
still another embodiment, the compound or a salt thereof, wherein
R.sup.1 is 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, which is substituted with a group selected
from the group consisting of carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl, in a further still
another embodiment, the compound or a salt thereof, wherein R.sup.1
is 1,2,4-oxadiazol-3-yl, which is substituted with a group selected
from the group consisting of carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl, in a further still
another embodiment, the compound or a salt thereof, wherein R.sup.1
is 1,2,4-oxadiazol-5-yl which is substituted with a group selected
from the group consisting of carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl, in a further still
another embodiment, the compound or a salt thereof, wherein R.sup.1
is 1,3,4-oxadiazol-2-yl which is substituted with a group selected
from the group consisting of carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, and 2-hydroxyethylcarbamoyl. (2-2) The compound
or a salt thereof, wherein R.sup.1 is --N(lower
alkylene-cycloalkyl)-C(O)--R.sup.11, in another embodiment, the
compound or a salt thereof, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)--R.sup.11, in a further still another
embodiment, the compound or a salt thereof, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is lower
alkylene-O-lower alkylene-OR.sup.0 or lower)
alkylene-N(R.sup.0).sub.2, in a further still another embodiment,
the compound or a salt thereof, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is
2-methoxyethoxymethyl or N,N-dimethylaminomethyl, in a further
still another embodiment, the compound or a salt thereof, wherein
R.sup.1 is --N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is a
heterocyclic group which may be substituted with a group selected
from the group consisting of lower alkyl, halogeno-lower alkyl,
--O--R.sup.0, --O-halogeno-lower alkyl, and oxo, in a further still
another embodiment, the compound or a salt thereof, wherein R.sup.1
is --N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is
tetrahydrofuran-2-yl, tetrahydropyran-4-yl, pyrazin-2-yl, or
2-oxoimidazolidin-1-yl, in a further still another embodiment, the
compound or a salt thereof, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is
tetrahydrofuran-2-yl or tetrahydropyran-4-yl, in a further still
another embodiment, the compound or a salt thereof, wherein R.sup.1
is --N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is
pyrazin-2-yl, and in a further still another embodiment, the
compound or a salt thereof, wherein R.sup.1 is
--N(cyclopropylmethyl)-C(O)--R.sup.11, and R.sup.11 is
2-oxoimidazolidin-1-yl.
[0086] (3)The compound or a salt thereof, wherein n is 0.
[0087] (4) The compound or a salt thereof, wherein X.sup.1 is N and
X.sup.2 is N, in another embodiment, the compound or a salt
thereof, wherein X.sup.1 is C(H) and X.sup.2 is N, and in a still
another embodiment, the compound or a salt thereof, wherein X.sup.1
is N and X.sup.2 is C(H).
[0088] (5) (5-1) The compound or a salt thereof, wherein R.sup.3 is
--O--R.sup.31, in another embodiment, the compound or a salt
thereof, wherein R.sup.3 is --O-lower alkyl, --O-halogeno-lower
alkyl, --O-lower alkylene-OR.sup.0, --O-(cycloalkyl lower which may
be substituted with lower)alkylene-OR.sup.0), or --O-lower
alkylene-aryl, in a still another embodiment, the compound or a
salt thereof, wherein R.sup.3 is --O-(lower alkyl) or
--O-(lower)alkylene-OR.sup.0), in a further still another
embodiment, the compound or a salt thereof, wherein R.sup.3 is
isopropoxy, 1-hydroxypropan-2-yloxy, or 1-methoxypropan-2-yloxy, in
a further still another embodiment, the compound or a salt thereof,
wherein R.sup.3 is isopropoxy, in a further still another
embodiment, the compound or a salt thereof, wherein R.sup.3 is
1-hydroxypropan-2-yloxy, and in a further still another embodiment,
the compound or a salt thereof, wherein R.sup.3 is
1-methoxypropan-2-yloxy. (5-2) The compound or a salt thereof,
wherein R.sup.3 is --N(lower alkylene-cycloalkyl)-C(O)-lower alkyl,
in another embodiment, the compound or a salt thereof, wherein
R.sup.3 is --N(cyclopropylmethyl)-C(O)-lower alkyl, and in a still
another embodiment, the compound or a salt thereof, wherein R.sup.3
is N-cyclopropylmethyl-N-acetylamino.
[0089] (6) The compounds or salts thereof including the
combinations of two or more of the groups as described in (1) to
(5).
[0090] Furthermore, examples of specific embodiments including the
combinations of two or more of the groups as described in (1) to
(5) as described in (6) include (a) to (f) below.
[0091] (a) The compound of the formula (I) or a salt thereof,
wherein R.sup.1 is --N(lower alkylene-cycloalkyl)-C(O)--R.sup.11 or
R.sup.12.
[0092] (b) The compound of the formula (I) or a salt thereof as
described in (a), wherein Ring A is pyrazol-3-yl, thiazol-2-yl, or
1,2,4-thiadiazol-5-yl, each of which may be substituted with lower
alkyl which may be substituted with a hydroxyl group.
[0093] (c) The compound of the formula (I) or a salt thereof as
described in (b), wherein R.sup.3 is --O-lower alkyl,
--O-halogeno-lower alkyl, --O-lower alkylene-OR.sup.0,
--O-(cycloalkyl which may be substituted with
lower)alkylene-OR.sup.0), --O-lower alkylene-aryl, or --N(lower
alkylene-cycloalkyl)-C(O)-lower alkyl.
[0094] (d) The compound as described in (c), wherein X.sup.1 is
C(H) and X.sup.2 is N, or X.sup.1 is N and X.sup.2 is N.
[0095] (e) The compound as described in (d), wherein n is 0.
[0096] (f) The compound as described in (e), wherein R.sup.1 is
1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, each of which is substituted with a group
selected from the group consisting of lower alkylene-OR.sup.0,
--C(O)N(R.sup.0).sub.2, --C(O)N(R.sup.0)-lower alkylene-OR.sup.0,
and --C(O)N(R.sup.0)-cycloalkyl.
[0097] (f) The compound as described in (e), wherein R.sup.1 is
N(cyclopropylmethyl)-C(O)-lower alkylene-O-lower alkylene-OR.sup.0,
--N(cyclopropylmethyl)-C(O)-lower alkylene-N(R.sup.0).sub.2, or
--N(cyclopropylmethyl)-C(O)-(heterocyclic group which may be
substituted with a group selected from the group consisting of
lower alkyl, halogeno-lower alkyl, --O--R.sup.0, --O-halogeno-lower
alkyl, and oxo).
[0098] Examples of the specific compounds included in the compound
of the formula (I) or a salt thereof include the following
compounds:
[0099]
3-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yrazin-2-yl)-N,N-dimethyl-1,2,4-oxadiazole-5-carboxamide,
[0100]
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy}pyrazin-2-yl)-2-oxoimidazolidine-1-carboxamide,
[0101]
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy}pyrazin-2-yl)pyrazine-2-carboxamide,
[0102]
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy}pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxamide,
[0103]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yrazin-2-yl)-N,N-dimethyl-1,3,4-oxadiazole-2-carboxamide,
[0104]
3-[(5-{(cyclopropylmethyl)[(2-methoxyethoxy)acetyl]amino}pyrazin-2--
yl)oxy]-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide,
[0105]
(2R)-N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyraz-
ol-3-yl)carbamoyl]phenoxy}pyrazin-2-yl)tetrahydrofuran-2-carboxamide,
[0106]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yridin-2-yl)-1,2,4-oxadiazole-3-carboxamide,
[0107]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yridin-2-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide,
[0108]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yridin-2-yl)-N,N-dimethyl-1,2,4-oxadiazole-3-carboxamide,
[0109]
N-(5-{3-[acetyl(cyclopropylmethyl)amino]-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy}pyrazin-2-yl)-N-(cyclopropylmethyl)tetrahydro-2H-pyra-
n-4-carboxamide,
[0110]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yridin-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide,
[0111]
N-(2-hydroxyethyl)-5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)-
carbamoyl]phenoxy}pyridin-2-yl)-1,2,4-oxadiazole-3-carboxamide,
[0112]
3-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy)pyridin-2-yl]-N,N-dimethyl-1,2,4-oxadiazole-5-carboxa-
mide,
[0113]
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}p-
yrazin-2-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide,
[0114]
N-(cyclopropylmethyl)-N-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-5-[(-
1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy)pyrazin-2-yl]tetrahydro-2H-pyra-
n-4-carboxamide,
[0115]
5-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxamide,
[0116]
5-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxamide,
[0117]
3-[(5-{(cyclopropylmethyl)[(2-methoxyethoxy)acetyl]amino}pyrazin-2--
yl)oxy]-5-{[(2S)-1-hydroxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)ben-
zamide,
[0118]
3-({5-[(cyclopropylmethyl)(N,N-dimethylglycyl)amino]pyrazin-2-yl}ox-
y)-5-{[(2S)-1-methoxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamid-
e,
[0119]
(2R)-N-(cyclopropylmethyl)-N-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-
-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy)pyrazin-2-yl]tetrahydrofur-
an-2-carboxamide, and
[0120] salts thereof.
[0121] The compound of the formula (I) may exist in the form of
tautomers or geometrical isomers depending on the kind of
substituents. In the present specification, the compound of the
formula (I) shall be described in only one form of isomer, yet the
present invention includes other isomers, isolated forms of the
isomers, or a mixture thereof.
[0122] In addition, the compound of the formula (I) may have
asymmetric carbon atoms or axial asymmetry in some cases, and it
may exist in the form of optical isomers based thereon. The present
invention includes both isolated optical isomers of the compound of
the formula (I) and a mixture thereof.
[0123] Moreover, the present invention also includes a
pharmaceutically acceptable prodrug of the compound represented by
the formula (I). The pharmaceutically acceptable prodrug is a
compound having a group that can be converted into an amino group,
a hydroxyl group, a carboxyl group, or the like through solvolysis
or under physiological conditions. Examples of the group forming
the prodrug include the groups described in Prog. Med., 5,
2157-2161 (1985) and "Pharmaceutical Research and Development"
(Hirokawa Publishing Company, 1990), Vol. 7, Drug Design,
163-198.
[0124] Furthermore, the salt of the compound of the formula (I) is
a pharmaceutically acceptable salt of the compound of the formula
(I) and may form an acid addition salt or a salt with a base
depending on the kind of substituents. Specific examples thereof
include acid addition salts with inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, nitric acid, phosphoric acid, and the like, and with organic
acids such as formic acid, acetic acid, propionic acid, oxalic
acid, malonic acid, succinic acid, fumaric acid, maleic acid,
lactic acid, malic acid, mandelic acid, tartaric acid,
dibenzoyltartaric acid, ditolyltartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like,
and salts with inorganic bases such as sodium, potassium,
magnesium, calcium, aluminum, and the like or with organic bases
such as methylamine, ethylamine, ethanolamine, lysine, ornithine,
and the like, salts with various amino acids and amino acid
derivatives such as acetylleucine and the like, or ammonium salts,
etc.
[0125] In addition, the present invention also includes various
hydrates or solvates, and polymorphic crystalline substances of the
compound of the formula (I) and salts thereof. In addition, the
present invention also includes compounds labeled with various
radioactive or non-radioactive isotopes.
[0126] (Preparation Methods)
[0127] The compound of the formula (I) and a salt thereof can be
prepared using the characteristics based on the basic structure or
the type of substituents thereof and by applying various known
synthesis methods. During the preparation, replacing the relevant
functional group with a suitable protective group (a group that can
be easily converted into the relevant functional group) at the
stage from starting material to an intermediate may be effective
depending on the type of the functional group in the preparation
technology in some cases. The protective group for such a
functional group may include, for example, the protective groups
described in "Greene's Protective Groups in Organic Synthesis
(4.sup.th Ed., 2006)", P. G M. Wuts and T. W. Greene, and one of
these may be suitably selected and used depending on the reaction
conditions. In this kind of method, a desired compound can be
obtained by introducing the protective group, by carrying out the
reaction and by eliminating the protective group as necessary.
[0128] In addition, the prodrug of the compound of the formula (I)
can be prepared by introducing a specific group at the stage from a
starting material to an intermediate, just as in the case of the
above-mentioned protective group or by further carrying out the
reaction using the obtained compound of the formula (I). The
reaction can be carried out using methods known to those skilled in
the art, such as ordinary esterification, amidation, dehydration,
and the like.
[0129] Hereinbelow, the representative preparation methods for the
compound of the formula (I) will be described. Further, the
preparation methods of the present invention are not limited to the
examples as shown below.
[0130] Furthermore, a desired functional group can be introduced by
carrying out functional group conversion that is apparent to a
person skilled in the art, such as amidation, alkylation,
hydrolysis, esterification, and the like, with the prepared
compounds or at the stage for a preparation intermediate, or by
carrying out the process in any order apparent to a person skilled
in the art. For example, in the following first production process,
R.sup.1 can be introduced into the compound of the present
invention by preparing 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
or 1,3,4-oxadiazol-2-yl, each of which may be substituted with
lower alkyl ester, and then converting lower alkyl ester into
amide. Further, for example, in the following first production
process, R.sup.1 can be introduced into the compound of the present
invention by preparing a secondary amino substituted with
halogeno-lower alkyl or lower alkylene-cycloalkyl, and then
introducing carbonyl or sulfonyl into amino. In addition, for
example, in the following first production process, an amide
substituent on a substituted benzene ring of R.sup.3 can be
introduced into the compound of the present invention by preparing
carboxylic acid or lower alkyl ester, and then converting
carboxylic acid or lower alkyl ester into amide.
[0131] (Production Process 1)
##STR00002##
[0132] (wherein Lv represents a leaving group).
[0133] The present preparation is a method for preparing the
compound (I) of the present invention by the reaction of a compound
1-a with a compound 1-b.
[0134] Here, examples of the leaving group include halogen atoms
such as fluorine, chlorine, bromine, and the like; lower
alkanesulfonyloxy which may be substituted, such as
methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy,
and the like; benzenesulfonyloxy which may be substituted, such as
benzenesulfonyloxy, 4-methylbenzenesulfonyloxy,
4-bromobenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, and the like;
etc.
[0135] In this reaction, the compound 1-a and the compound 1-b in
equivalent amounts, or either thereof in an excess amount are used,
and a mixture thereof is stirred in a range of from cooling to
heating to reflux, in a certain embodiment at 0.degree. C. to
80.degree. C., usually for about 0.1 hours to 5 hours, in a solvent
which is inert to the reaction or without a solvent. The solvent as
used herein is not particularly limited, but examples thereof
include aromatic hydrocarbons such as benzene, toluene, xylene, and
the like, ethers such as diethyl ether, tetrahydrofuran (THF),
dioxane, dimethoxyethane, and the like, halogenated hydrocarbons
such as dichloromethane, 1,2-dichloroethane, chloroform, and the
like, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl
acetate, acetonitrile, and a mixture thereof. It may be in some
cases advantageous for smooth progress of the reaction to carry out
the reaction in the presence of organic bases such as
triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and
the like, or inorganic bases such as potassium carbonate, sodium
carbonate, potassium hydroxide, and the like.
[0136] Further, in the case where R.sup.1 in the compound 1-a or
the compound (I) is 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl, each of which may be substituted, preparation
can be conducted using a cyclization reaction that is apparent to a
person skilled in the art from the corresponding carboxylic acid
derivative. Specifically, the methods described in Preparation
Examples or Examples as described later may be exemplified, and
modified methods thereof, methods equivalent thereto, or the like
may also be employed. That is, conversion from the carboxylic acid
derivative into 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, or
1,3,4-oxadiazol-2-yl may be carried out before the step of the
first production process or after the step of the first production
process.
[0137] In the preparation method, the starting compound can be
prepared by using, for example, the method described in Preparation
Examples as described later, a known method, or a modified method
thereof.
[0138] The compounds of the formula (I) can be isolated and
purified as free compounds, salts, hydrates, solvates, or
polymorphic crystalline substances thereof. The salts of the
compound of the formula (I) can be prepared by carrying out the
treatment of a conventional salt forming reaction.
[0139] Isolation and purification are carried out by employing
ordinary chemical operations such as extraction, fractional
crystallization, various types of fractional chromatography, and
the like.
[0140] Various isomers can be prepared by selecting an appropriate
starting compound or separated by using the difference in the
physicochemical properties between the isomers. For example, the
optical isomers can be obtained by means of a general optical
resolution method for racemic products (for example, fractional
crystallization for inducing diastereomer salts with optically
active bases or acids, chromatography using a chiral column or the
like, and others), and further, the isomers can also be prepared
from an appropriate optically active starting compound.
[0141] The pharmacological activity of the compound of the formula
(I) was confirmed by the tests shown below.
[0142] Test Example 1 Measurement of Glucokinase (GK)
Activation
[0143] The present test was carried out in accordance with the
method described in Science 301: 370-373, 2003 with partial
modification, and is summarized as below.
[0144] First, cloning of GK (GenBank No. AK122876) was carried out.
PCR was carried out using 5'-TAGAATTCATGGCGATGGATGTCACAAG-3' (SEQ
ID NO: 1) and 5'-ATCTCGAGTCACTGGCCCAGCATACAG-3' (SEQ ID NO: 2) as
primers, and pME18S-FL3-Glucokinase isoform 2 as a template. The
resulting reaction product was TA-cloned into a pGEM-T easy vector,
and then digested with EcoRI and XhoI, and the fragment was ligated
to a pGEX-5X-1 vector digested in the same manner. Using this
plasmid DNA (pGEX-human Glucokinase 2), a recombinant human liver
type GK (GST-hGK2) fused with GST (Glutathione S-transferase) was
expressed in E. coli (strain BL21), and purified by Glutathione
Sepharose.
[0145] The reaction of GK was carried out at 27.degree. C. on a
96-well plate. First, 1 .mu.L of a test compound diluted with
dimethylsulfoxide (DMSO) (final concentration of 10 .mu.M) was
added to a 89 .mu.L of an enzyme mixed liquid (25 mM HEPES pH 7.4,
25 mM KCl, 2 mM MgCl.sub.2, 1 mM ATP, 0.1% BSA, 1 mM DTT, 1 mM NADP
(nicotinamide adenine dinucleotide phosphate), 2.5 U/mL
glucose-6-phosphate dehydrogenase, GST-hGK2 adjusted to
.DELTA.OD.sub.Cont as described later to be about 0.05 to 0.10, all
of which are final concentrations). Subsequently, 10 .mu.L of a
substrate solution (final concentration of 5 mM glucose) was added
thereto to initiate the reaction. In order to quantify a final
product NADPH, an absorbance at a wavelength of 340 nm was
measured, and the GK activation (%) of the test compound was
calculated from the increase (DOD) in the absorbance during the
first 10 minutes after the initiation of the reaction, using the
following formula.
GK activation
(%)=[(.DELTA.OD.sub.Test)-(.DELTA.OD.sub.Cont)]/(.DELTA.OD.sub.Cont).time-
s.100
[0146] .DELTA.OD.sub.Test: .DELTA.OD at the test compound
[0147] .DELTA.OD.sub.Cont: .DELTA.OD at DMSO
[0148] The results of the measurement are shown in Table 1.
Further, Ex indicates Example compound Number.
TABLE-US-00001 TABLE 1 Ex GK activation (%) 1 295 2 338 3 380 9 319
10 380 23 347 24 269 29 287 67 498 74 298 75 276 98 498 101 345 110
338 119 376 128 338 130 502 138 316 156 237 158 237 162 306
[0149] Test Example 2 Oral Glucose Loading Test in Normal Mice
[0150] The test compound was dissolved in a solvent (5% Cremophor,
5% aqueous DMSO solution), 10 mg/kg of the test compound was orally
administered to ICR mice after fasting overnight, and after 30
minutes, oral glucose loading was carried out. Immediately before
the administration of the test compound, immediately before the
glucose loading, and 0.25, 0.5, 1, and 2 hours after the glucose
loading, blood was collected and blood glucose levels were
measured. An AUC lowering rate (%) of the blood glucose levels from
immediately before the glucose loading to 2 hours after the glucose
loading with respect to that of the solvent control was
calculated.
[0151] The results are shown in Table 2.
TABLE-US-00002 TABLE 2 Ex Blood glucose level lowering rate (%) 1
37 2 59 3 64 9 46 10 61 23 52 24 49 29 49 67 57 74 45 75 48 98 54
101 48 110 43 119 40 128 47 130 65 138 61 156 18 158 29 162 25
[0152] Test Example 3 Oral Glucose Loading Test in High Fat Diet
Loading Mice
[0153] The test compound is dissolved in a solvent (5% Cremophor,
5% aqueous DMSO solution), and orally administered to C57BL/6 mice
after loading a high fat diet for about 30 days and then fasting
overnight, and after 30 minutes, oral glucose loading was carried
out. Immediately before the administration of the test compound,
immediately before the glucose loading, and 0.25, 0.5, 1, and 2
hours after the glucose loading, blood is collected and blood
glucose levels were measured. An AUC lowering rate (%) of the blood
glucose levels from immediately before the glucose loading to 2
hours after the glucose loading with respect to that of the solvent
control is calculated.
[0154] As described above, a glucose level lowering action of the
compound of the present invention on the high fat diet loading mice
can be evaluated.
[0155] Test Example 4 Oral Glucose Loading Test in Normal Rats
[0156] The test compound was dissolved in a solvent (5% Cremophor,
5% aqueous DMSO solution), 3 mg/kg of the test compound was orally
administered to SD rats after fasting overnight, and after 30
minutes, oral glucose loading was carried out. Immediately before
the administration of the test compound, immediately before the
glucose loading, and 0.5, 1, and 2 hours after the glucose loading,
blood was collected and blood glucose levels were measured. An AUC
lowering rate (%) of the blood glucose levels from immediately
before the glucose loading to 2 hours after the glucose loading
with respect to that of the solvent control was calculated.
[0157] The results are shown in Table 3.
TABLE-US-00003 TABLE 3 Ex Blood glucose level lowering rate (%) 1
28 2 39 9 19 23 45 29 33
[0158] From the above test results, it was confirmed that the
compound of the formula (I) has a GK activation action and a blood
glucose level lowering action. In addition, the compound can be
used as an active ingredient of a pharmaceutical composition for
preventing and/or treating diabetes, type 2 diabetes mellitus,
obesity, or metabolic syndrome, and the like.
[0159] A pharmaceutical composition containing one or more kinds of
the compound of the formula (I) or a salt thereof as an active
ingredient can be prepared using excipients that are usually used
in the art, that is, excipients for pharmaceutical preparation,
carriers for pharmaceutical preparation, and the like according to
the methods usually used.
[0160] Administration can be accomplished either by oral
administration via tablets, pills, capsules, granules, powders,
solutions, and the like, or parenteral administration, such as
injections such as intraarticular, intravenous, and intramuscular
injections, suppositories, ophthalmic solutions, eye ointments,
transdermal solutions, ointments, transdermal patches, transmucosal
solutions, transmucosal patches, inhalers, and the like.
[0161] The solid composition for oral administration is used in the
form of tablets, powders, granules, or the like. In such a solid
composition, one or more active ingredient(s) are mixed with at
least one inactive excipient. In a conventional method, the
composition may contain inactive additives, such as a lubricant, a
disintegrating agent, a stabilizer, or a solubilization assisting
agent. If necessary, tablets or pills may be coated with sugar or a
film of a gastric-soluble or enteric coating substance.
[0162] The liquid composition for oral administration contains
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, elixirs, or the like, and also contains generally used
inert diluents, for example, purified water or ethanol (EtOH). In
addition to the inert diluent, the liquid composition may also
contain adjuvants, such as a solubilization assisting agent, a
moistening agent, and a suspending agent, sweeteners, flavors,
aromatics, or antiseptics.
[0163] The injections for parenteral administration include sterile
aqueous or non-aqueous solutions, suspensions, or emulsions. The
aqueous solvent includes, for example, distilled water for
injection or physiological saline. Examples of the non-aqueous
solvent include alcohols such as ethanol. Such a composition may
further contain a tonicity agent, an antiseptic, a moistening
agent, an emulsifying agent, a dispersing agent, a stabilizer, or a
solubilization assisting agent. These are sterilized, for example,
by filtration through a bacteria retaining filter, blending of a
bactericide, or irradiation. In addition, these can also be used by
preparing a sterile solid composition, and dissolving or suspending
it in sterile water or a sterile solvent for injection prior to its
use.
[0164] The agent for external use includes ointments, plasters,
creams, jellies, poultices, sprays, lotions, eye drops, eye
ointments, and the like. The agents contain generally used ointment
bases, lotion bases, aqueous or non-aqueous solutions, suspensions,
emulsions, and the like.
[0165] As the transmucosal agents such as an inhaler, a transnasal
agent, and the like, those in the form of a solid, liquid, or
semi-solid state are used, and can be prepared in accordance with a
conventionally known method. For example, a known excipient, and
also a pH adjusting agent, an antiseptic, a surfactant, a
lubricant, a stabilizer, a thickening agent, or the like may be
appropriately added thereto. For their administration, an
appropriate device for inhalation or blowing can be used. For
example, a compound may be administered alone or as a powder of
formulated mixture, or as a solution or suspension in combination
with a pharmaceutically acceptable carrier, using a known device or
sprayer, such as a measured administration inhalation device, and
the like. A dry powder inhaler or the like may be for single or
multiple administration use, and a dry powder or a
powder-containing capsule may be used. Alternatively, this may be
in a form of an appropriate ejection agent such as a pressurized
aerosol spray which uses a suitable gas such as chlorofluoroalkane,
hydrofluoroalkane, carbon dioxide, and the like.
[0166] In oral administration, the daily dose is generally from
about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more
preferably 0.1 to 10 mg/kg, per body weight, administered in one
portion or in 2 to 4 separate portions. In the case of intravenous
administration, the daily dose is suitably administered from about
0.0001 to 10 mg/kg per body weight, once a day or two or more times
a day. In addition, a transmucosal agent is administered at a dose
from about 0.001 to 100 mg/kg per body weight, once a day or two or
more times a day. The dose is appropriately decided in response to
the individual case by taking the symptoms, the age, and the
sexuality, and the like into consideration.
[0167] Although varying depending on administration routes, dosage
forms, administration sites, or the types of excipients and
additives, the pharmaceutical composition of the present invention
contains 0.01 to 100% by weight, and in a certain embodiment, 0.01
to 50% by weight of one or more kinds of the compound of the
formula (I) or a salt thereof, which is an active ingredient.
[0168] The compound of the formula (I) or a salt thereof can be
used in combination with various agents for treating or preventing
the diseases, in which the compound of the formula (I) or a salt
thereof is considered effective, as described above. The combined
use may be administered simultaneously or separately and
continuously, or at a desired time interval. The preparations to be
administered simultaneously may be prepared individually or may be
a pharmaceutical composition including various agents for treating
or preventing the diseases, in which the compound of the formula
(I) or a salt thereof is considered effective, as described above,
and the compound of the formula (I) or a salt thereof.
EXAMPLES
[0169] Hereinbelow, the preparation methods for the compound of the
formula (I) or a salt thereof will be described in more detail with
reference to Examples, but the present invention is not limited to
the compounds described in the Examples as described below.
Furthermore, the production processes for the starting compounds
will be described in Preparation Examples. Further, the preparation
methods for the compound of the formula (I) are not limited to the
preparation methods of the specific Examples as below, and the
compound of the formula (I) can be prepared by any combination of
the preparation methods or the methods that are apparent to a
person skilled in the art.
Preparation Example 1
[0170] To a mixture of
3-hydroxy-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (492
mg), potassium carbonate (445 mg), and N-methylpyrrolidone (NMP) (4
mL) was added a solution of 5-chloropyrazine-2-carbonitrile in NMP
(3 mL) under ice-cooling, followed by stirring at room temperature
for 4 hours and at 50.degree. C. for 20 minutes. Diethyl ether (20
mL) and water (20 mL) were added thereto to carry out liquid
separation, the organic layer was washed with water (20 mL) and
saturated brine (20 mL) in this order, and the aqueous layer was
extracted again with diethyl ether (20 mL). The combined organic
layer was dried over anhydrous magnesium sulfate and then filtered,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate=1:1 to 1:2) to obtain
3-[(5-cyanopyrazin-2-yl)oxy]-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)ben-
zamide (632 mg) as a light yellow oil.
Preparation Example 2
[0171] To a solution of
3-[(5-cyanopyrazin-2-yl)oxy]-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)ben-
zamide (615 mg) in methanol (5 mL) was added a 50% aqueous
hydroxylamine solution (200 .mu.L) under ice-cooling, followed by
stirring at room temperature for 1 hour. Water (5 mL) was added
thereto, and the insoluble material was collected by filtration,
washed with methanol, and dried under reduced pressure to obtain
3-{[5-(N'-hydroxycarbamimidoyl)pyrazin-2-yl]oxy}-5-isopropoxy-N-(1-methyl-
-1H-pyrazol-3-yl)benzamide (618 mg) as a white solid.
Preparation Example 3
[0172]
3-{[5-(N'-Hydroxycarbamimidoyl)pyrazin-2-yl]oxy}-5-isopropoxy-N-(1--
methyl-1H-pyrazol-3-yl)benzamide (316 mg) was suspended in a mixed
solvent of dioxane (2 mL)-chloroform (2 mL), and triethylamine (260
.mu.L) and ethylchloro(oxo)acetate (120 .mu.L) were added thereto
in an ice bath, followed by stirring at room temperature for 45
minutes and at 80.degree. C. for 4 hours. The reaction mixture was
cooled to room temperature, and triethylamine (64 .mu.L) and
ethylchloro(oxo)acetate (30 A) were added thereto, followed by
stirring at 80.degree. C. for 2 hours and at 100.degree. C. for 1
hour. The reaction mixture was cooled to room temperature, and
ethyl acetate and water were added thereto to carry out liquid
separation. The organic layer was washed with a saturated aqueous
sodium hydrogen carbonate solution and saturated brine in this
order, dried over anhydrous magnesium sulfate, and then filtered,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate=1:1 to 1:2) to obtain ethyl
3-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazin-
-2-yl)-1,2,4-oxadiazole-5-carboxylate (123 mg) as a white amorphous
substance.
Preparation Example 4
[0173] Methyl 3-(4-cyanophenoxy)benzoate (1.83 g), methanol (20
mL), and THF (20 mL) were mixed, and a 1 M aqueous sodium hydroxide
solution (8.70 mL) was added thereto, followed by stirring for 1
hour and leaving to stand overnight. The reaction mixture was
concentrated under reduced pressure, and water and 1 M hydrochloric
acid was added thereto, followed by extraction with ethyl acetate.
The organic layer was washed with water and a saturated aqueous
sodium chloride solution, and dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure to
obtain 3-(4-cyanophenoxy)benzoic acid (1.55 g) as a white
solid.
Preparation Example 5
[0174] 3-(4-Cyanophenoxy)benzoic acid (1.55 g),
1-methyl-1H-pyrazole-3-amine (1.26 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)
(1.86 g), 1-hydroxybenzotriazole (HOBt) (1.31 g), and DMF (30 mL)
were mixed, followed by stirring at room temperature for 3 hours.
To the reaction mixture was added water, followed by extraction
with ethyl acetate. The organic layer was washed with water, a
saturated aqueous sodium hydrogen carbonate solution, 1 M
hydrochloric acid, and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography to obtain
3-(4-cyanophenoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.99 g)
as a white amorphous substance.
Preparation Example 6
[0175] To a mixture of 3-(benzyloxy)-5-(methoxycarbonyl)benzoic
acid (114 g) and tert-butyl alcohol (700 mL) were added
triethylamine (70 mL) and diphenylazide phosphate (100 mL),
followed by heating to 105.degree. C. and stirring for 2 hours.
After leaving to stand for cooling at room temperature, ethyl
acetate (700 mL) was added thereto, and the organic layer was
washed sequentially with water (700 mL), 1 M hydrochloric acid (700
mL), a saturated aqueous sodium hydrogen carbonate solution (700
mL), and saturated brine (500 mL), dried over anhydrous magnesium
sulfate, and then concentrated. To the residue was added
hexane/diethyl ether=1/2 (150 mL), followed by stirring for a
while, and then the resulting precipitate was collected by
filtration and dried to obtain methyl
3-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]benzoate (94.6 g) as a
colorless solid.
Preparation Example 7
[0176] To a solution of methyl
3-(benzyloxy)-5-[(tert-butoxycarbonyl)amino]benzoate (50 g) in
dimethylformamide (250 mL) was added tert-butoxypotassium (19 g)
under ice-cooling, followed by stirring for a while (yellow
solution). Then, bromomethylcyclopropane (18 mL) was added thereto
at an internal temperature of 15.degree. C. or lower, followed by
stirring for 20 minutes, and then stirring at room temperature for
3 hours. Water (800 mL) and ethyl acetate (400 mL) were added
thereto, and the organic layer was washed with water (400 mL), a
saturated aqueous sodium hydrogen carbonate solution (500 mL), 1 M
hydrochloric acid (500 mL), and saturated brine (400 mL), and dried
over anhydrous magnesium sulfate. Then, the solvent was evaporated
under reduced pressure to obtain methyl
3-(benzyloxy)-5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]benzoate
(57.5 g) as a yellow oily substance.
Preparation Example 8
[0177] To a solution of methyl
3-(benzyloxy)-5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]benzoate
(1.02 g) in ethanol (15 mL)-THF (15 mL) were added cyclohexene (5.0
mL) and 20% palladium hydroxide-carbon powder (30 wt %, 232 mg),
followed by heating to reflux for 1.5 hours. After filtration using
Celite, the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=83:17 to 67:33) to obtain methyl
3-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-5-hydroxybenzoate
(765 mg) as a colorless liquid.
Preparation Example 9
[0178] A mixture of methyl
3-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-5-hydroxybenzoate
(1.38 g), potassium carbonate (1.19 g), 4-fluorobenzonitrile (624
mg), and NMP (15 mL) was heated and stirred at 100.degree. C. for 2
hours and 30 minutes. The reaction mixture was cooled to room
temperature, and diethyl ether (75 mL) and water (75 mL) were added
thereto to carry out liquid separation. The organic layer was
washed with a 0.2 M aqueous sodium hydroxide solution (75 mL),
water (75 mL), and saturated brine (75 mL) in this order, dried
over anhydrous magnesium sulfate, and then filtered, and the
filtrate was concentrated under reduced pressure to obtain methyl
3-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-5-(4-cyanophenoxy)benzo-
ate (1.38 g).
Preparation Example 10
[0179] To a solution of methyl
3-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-5-(4-cyanophenoxy)benzo-
ate (50 mg) in dichloromethane (1 mL) was added trifluoroacetic
acid (180 .mu.L), followed by stirring at room temperature for 2
hours. A saturated aqueous sodium hydrogen carbonate solution was
added thereto until bubbles were not generated, followed by
extraction with ethyl acetate (15 mL). The organic layer was washed
with a saturated aqueous sodium hydrogen carbonate solution (15 mL)
and saturated brine (15 mL) in this order, dried over anhydrous
magnesium sulfate, and then filtered, and the filtrate was
concentrated under reduced pressure to obtain methyl
3-(4-cyanophenoxy)-5-[(cyclopropylmethyl)amino]benzoate (33
mg).
Preparation Example 11
[0180] To a mixed liquid of methyl
3-(4-cyanophenoxy)-5-[(cyclopropylmethyl)amino]benzoate (980 mg),
chloroform (1 mL), and pyridine (1 mL) was added acetic anhydride
(1 mL), followed by stirring at room temperature for 17 hours. To
the reaction mixture were added diethyl ether (20 mL) and water (20
mL) to carry out liquid separation, and the organic layer was
washed with 0.2 M hydrochloric acid (20 mL), water (20 mL) and
saturated brine (20 mL) in this order, and dried over anhydrous
magnesium sulfate. The filtrate was concentrated under reduced
pressure to obtain methyl
3-[acetyl(cyclopropylmethyl)amino]-5-(4-cyanophenoxy)benzoate (1.13
g).
Preparation Example 12
[0181] 5-Fluoropyridine-2-carboxylic acid hydrochloride (13.15 g)
and dichloromethane (130 mL) were mixed, and oxalyl chloride (9.85
mL) and DMF (0.570 mL) were added thereto, followed by stirring for
1 hour. The reaction mixture was concentrated under reduced
pressure, and toluene was added thereto, followed by concentration
under reduced pressure. The obtained residue and dichloromethane
(260 mL) were mixed, and ethyl (2E)-amino(hydroxyimino)acetate
(10.78 g) was added thereto under ice-cooling, followed by stirring
for 30 minutes. The reaction mixture was diluted with chloroform,
washed with water, a saturated aqueous sodium hydrogen carbonate
solution, and a saturated aqueous sodium chloride solution, and
dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue was washed
with ethyl acetate and collected by filtration to obtain a beige
solid.
[0182] The obtained solid and NMP (130 mL) were mixed, and
4-methylbenzenesulfonic acid hydrate (705 mg) was added thereto,
followed by stirring at an oil bath temperature of 130.degree. C.
for 1 hour. 4-Methylbenzenesulfonic acid hydrate (705 mg) was added
thereto, followed by stirring at an oil bath temperature of
130.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature and diluted with ethyl acetate, washed with water, a 1
M aqueous sodium hydroxide solution, and a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The obtained
residue was washed with diethyl ether and collected by filtration
to obtain ethyl
5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate (7.95 g) as
a white solid.
Preparation Example 13
[0183] 3-Hydroxy-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide
(4.00 g), ethyl
5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate (3.45 g),
potassium carbonate (4.02 g), and DMF (40 mL) were mixed, followed
by stirring at an oil bath temperature of 60.degree. C. for 1 hour
and stirring at an oil bath temperature of 80.degree. C. for 1.5
hours. Ethyl
5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazole-3-carboxylate (345 mg)
was added thereto, followed by stirring at an oil bath temperature
of 80.degree. C. for 1 hour. The reaction mixture was cooled to
room temperature and diluted with ethyl acetate, washed with water
and a saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=7:3 to 3:7) to obtain ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxylate (6.35 g) as a white amorphous
substance.
Preparation Example 14
[0184] 3-Hydroxy-5-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide
(2.41 g), ethyl 5-fluoropyridine-2-carboxylate (1.61 g), and
potassium carbonate (3.03 g), NMP (50 mL) were mixed, followed by
stirring at 110.degree. C. for 5 hours. The reaction mixture was
cooled to room temperature, and water was added thereto, followed
by extraction with ethyl acetate. The organic layer was washed with
a saturated aqueous sodium hydrogen carbonate solution and
saturated brine, and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure to obtain a light
yellow oily substance. The obtained light yellow oily substance,
methanol (30 mL), and a 5 M aqueous sodium hydroxide solution (3.5
mL) were mixed, followed by stirring at 60.degree. C. for 1 hour. 1
M hydrochloric acid was added thereto under ice-cooling to adjust
the pH to 4, and water (120 mL) was added thereto. While washing
with a solvent (methanol:water=4:1), the precipitated solid was
collected by filtration to obtain
5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxyl}pyridine--
2-carboxylic acid (3.24 g) as a white solid.
Preparation Example 15
[0185]
5-{3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyri-
dine-2-carboxylic acid (3.24 g) and DMF (30 mL) were mixed, and
EDCI (2.02 g), 1-hydroxy-7-azabenzotriazole (1.43 g), tert-butyl
hydrazinecarboxylate (1.51 g), and triethylamine (3.2 mL) were
added thereto, followed by stirring at room temperature overnight.
To the reaction mixture was added water, followed by extraction
with ethyl acetate. The organic layer was washed with a saturated
aqueous sodium hydrogen carbonate solution and saturated brine, and
dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure to obtain a light yellow oily
substance. To a solution of the obtained light yellow oily
substance in dichloromethane (30 mL) was added trifluoroacetic acid
(13 mL), followed by stirring at room temperature for 2 hours. The
reaction mixture was concentrated under reduced pressure. A
saturated aqueous sodium hydrogen carbonate solution was added
thereto to adjust the pH to 8, followed by addition of saturated
brine and extraction with a solvent (chloroform:isopropyl
alcohol=4:1) twice. The organic layer was dried over anhydrous
magnesium sulfate and the solvent was evaporated under reduced
pressure to obtain
3-{[6-hydrazinocarbonyl)pyridin-3-yl]oxy}-5-isopropoxy-N-(1-methyl-1H-pyr-
azol-3-yl)benzamide (3.43 g) as a light yellow amorphous
substance.
Preparation Example 16
[0186]
3-{[6-Hydrazinocarbonyl)pyridin-3-yl]oxy}-5-isopropoxy-N-(1-methyl--
1H-pyrazol-3-yl)benzamide (1.0 g) and THF (10 mL) were mixed,
triethylamine (0.82 mL) was added thereto, followed by addition of
ethyloxalyl chloride (0.33 mL) under ice-cooling and stirring for 1
hour under ice-cooling. To the reaction mixture were added water
and saturated brine under ice-cooling, followed by extraction with
a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was
dried over anhydrous magnesium sulfate and the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1, chloroform:methanol=1:0 to 10:1) to obtain ethyl
{2-[(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrid-
in-2-yl)carbonyl]hydrazino}(oxo)acetate (1.16 g) as a light yellow
amorphous substance.
Preparation Example 17
[0187] Into a solution of ethyl
{2-[(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrid-
in-2-yl)carbonyl]hydrazino}(oxo)acetate (1.16 g) in dichloromethane
(30 mL) was mixed pyridine (0.74 mL), and anhydrous
trifluoromethanesulfonic anhydride (0.75 mL) was added thereto
under ice-cooling and stirring for 30 minutes under ice-cooling. To
the reaction mixture was added water under ice-cooling, followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous ammonium chloride solution, a saturated aqueous
sodium hydrogen carbonate solution and saturated brine, and dried
over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) to
obtain ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,3,4-oxadiazole-2-carboxylate (572 mg) as a yellowish green
amorphous substance.
Preparation Example 18
[0188] To a solution of 5-chloropyrazine-2-carboxylic acid (2 g) in
dichloromethane (20 mL) were added DMF (0.05 mL) and oxalyl
chloride (1.3 mL), followed by stiffing at room temperature for 1
hour. The reaction mixture was concentrated under reduced pressure
and azeotroped with toluene. To the residue was added
dichloromethane (20 mL), followed by ice-cooling, and triethylamine
(4 mL) and ethyl (2E)-amino(hydroxy)iminoacetate (2 g) were added
thereto, followed by stirring at the same temperature for 15
minutes. To the reaction mixture was added a saturated aqueous
sodium hydrogen carbonate solution, followed by extraction with
chloroform. The solid remaining in the aqueous layer was collected
by filtration and dried under reduced pressure to obtain ethyl
(2E)-amino({[(5-chloropyrazin-2-yl)carbonyl]oxy}imino)acetate (1.4
g) as a colorless solid. Further, the organic layer was washed with
a saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure to
obtain ethyl
(2E)-amino({[(5-chloropyrazin-2-yl)carbonyl]oxy}imino)acetate (1.9
g) as a yellow solid.
Preparation Example 19
[0189] A mixture of ethyl
(2E)-amino({[(5-chloropyrazin-2-yl)carbonyl]oxy}imino)acetate (1.87
g), 4-methylbenzenesulfonic acid (172 mg), and dioxane (100 mL) was
stirred at 100.degree. C. for 10 hours. To the reaction mixture
were added ethyl acetate and water to carry out liquid separation,
and the organic layer was washed with a saturated aqueous sodium
hydrogen carbonate solution, and saturated brine in this order,
dried over anhydrous magnesium sulfate, and then filtered. The
filtrate was concentrated under reduced pressure to obtain ethyl
5-(5-chloropyrazin-2-yl)-1,2,4-oxadiazole-3-carboxylate (1.713 g)
as a white solid.
Preparation Example 20
[0190]
3-(Benzyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (2.52
g), DMF (25 mL), ethyl 1-bromocyclobutane carboxylate (1.52 mL),
and potassium carbonate (2.59 g) were mixed, followed by stirring
at an oil bath temperature of 80.degree. C. for 3 hours.
Furthermore, ethyl 1-bromocyclobutane carboxylate (1.52 mL) was
added thereto, followed by stirring at an oil bath temperature of
120.degree. C. for 8 hours. Further, ethyl 1-bromocyclobutane
carboxylate (1.52 mL) and potassium carbonate (2.59 g) were added
thereto, followed by stirring at an oil bath temperature of
120.degree. C. for 24 hours. The reaction mixture was cooled to
room temperature, and water was added thereto, followed by dilution
with ethyl acetate. The organic layer was washed with water, 1 M
hydrochloric acid, a 1 M aqueous sodium hydroxide solution, and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7:3 to 2:8) to obtain a
yellow amorphous substance.
[0191] The obtained amorphous substance and ethanol (50 mL) were
mixed, and a 1 M aqueous sodium hydroxide solution (16 mL) was
added thereto, followed by stirring at room temperature for 2
hours. Further, a 1 M aqueous sodium hydroxide solution (8 mL) was
added thereto, followed by stirring for 2 hours. The reaction
mixture was concentrated under reduced pressure, and 1 M
hydrochloric acid was added thereto, followed by extraction with
ethyl acetate. The organic layer was washed with water and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained solid was washed with diisopropyl
ether and collected by filtration to obtain
1-{3-(benzyloxy)-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}cyclobuta-
ne carboxylic acid (2.00 g) as a yellowish white solid.
Preparation Example 21
[0192]
1-{3-(Benzyloxy)-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}cyc-
lobutane carboxylic acid (2.00 g) and THF (40 mL) were mixed, and
CDI (924 mg) was added thereto, followed by stirring at an oil bath
temperature of 50.degree. C. for 1 hour. The reaction mixture was
ice-cooled, and water (4.2 mL) and sodium borohydride (539 mg) were
added thereto, followed by stirring for 30 minutes. To the reaction
mixture was added water, followed by extraction with ethyl acetate.
The organic layer was washed with a saturated aqueous sodium
chloride solution and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:3 to 2:8) to obtain
3-(benzyloxy)-5-{[1-(hydroxymethyl)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-
-3-yl)benzamide (1.58 g) as a white amorphous substance.
Preparation Example 22
[0193]
3-(Benzyloxy)-5-{[1-(hydroxymethyl)cyclobutyl]oxy}-N-(1-methyl-1H-p-
yrazol-3-yl)benzamide (1.57 g), DMF (20 mL), 1H-imidazole (603 mg),
and tert-butyl (chloro)dimethylsilane (1.28 g) were mixed, followed
by stirring at room temperature for 1 hour. The reaction mixture
was diluted with ethyl acetate, washed with water, a saturated
aqueous ammonium chloride solution, a saturated aqueous sodium
hydrogen carbonate solution, and a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:0 to 7:3) to obtain
3-(benzyloxy)-5-{[1-({[tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)be-
nzamide (1.81 g) as a colorless oily substance.
Preparation Example 23
[0194] 3-(Benzyloxy)-5-{[1-({[tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)be-
nzamide (1.81 g), 10% palladium/carbon (360 mg), and ethyl acetate
(25 m) were mixed, followed by stirring overnight under a hydrogen
atmosphere of 0.4 MPa. After filtration using Celite, the filtrate
was concentrated under reduced pressure. The obtained solid was
washed with hexane and collected by filtration to obtain
3-{[1-({[tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyraz-
ol-3-yl)benzamide (1.29 g) as a white solid.
Preparation Example 24
[0195] Ethyl 5-[5-(3-{[1-({[tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)c-
arbamoyl]phenoxy)pyrazin-2-yl]-1,2,4-oxadiazole-3-carboxylate (250
mg), and THF (5 mL) were mixed, and a 2 M methylamine/THF solution
(0.580 mL) was added thereto under ice-cooling, followed by
stirring for 30 minutes, warming to room temperature, and stirring
for 15 minutes. Further, a 2 M methylamine/THF solution (0.580 mL)
was added thereto, followed by stirring for 15 minutes. Further, a
2 M methylamine/THF solution (0.580 mL) was added thereto, followed
by stirring for 15 minutes. Further, a 2 M methylamine/THF solution
(0.580 mL) was added thereto, followed by stirring for 15 minutes.
The reaction mixture was diluted with ethyl acetate, washed with
water and a saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1 to 0:1) to
obtain 5-[5-(3-{[1-({[tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)c-
arbamoyl]phenoxy)pyrazin-2-yl]-N-methyl-1,2,4-oxadiazole-3-carboxamide
(162 mg) as a white amorphous substance.
Preparation Example 25
[0196] Ethyl
5-(3-{[1-(hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)carb-
amoyl]phenoxy)pyridine-2-carboxylate (415 mg), ethanol (10 mL), and
a 1 M aqueous sodium hydroxide solution (2.7 mL) were added,
followed by stirring at room temperature for 3 hours. To the
reaction mixture, 1 M hydrochloric acid (2.7 mL) and water were
added, followed by extraction with a mixed solution of
chloroform/isopropanol (4:1). The organic layer was washed with a
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
pressure. The obtained solid was washed with ethyl acetate and
collected by filtration to obtain
5-(3-{[1-(hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)carb-
amoyl]phenoxy)pyridine-2-carboxylic acid (267 mg) as a white
solid.
Preparation Example 26
[0197] tert-Butyl
5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazine-2-
-carboxylate (1.29 g) and dichloromethane (30 mL) were mixed, and
trifluoroacetic acid (4.35 mL) was added thereto, followed by
stirring at room temperature for 3 hours. The reaction mixture was
concentrated under reduced pressure, and toluene was added thereto,
followed by concentration under reduced pressure. To the obtained
residue was added ethyl acetate, followed by washing with a
saturated aqueous sodium hydrogen carbonate solution. The aqueous
layer was neutralized by the addition of 1 M hydrochloric acid and
extracted with a mixed solution of chloroform/isopropanol (4:1).
The organic layer was washed with water and the solvent was
evaporated under reduced pressure. The obtained residue was washed
with diisopropyl ether and collected by filtration to obtain
5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazine-2-
-carboxylic acid (797 mg) as a white solid.
Preparation Example 27
[0198]
5-{3-Isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyra-
zine-2-carboxylic acid (1.195 g) and DMF (24 mL) were mixed, and
EDCI (750 mg), 1-hydroxy-7-azabenzotriazole (532 mg), triethylamine
(1.28 mL), and tert-butylhydrazinecarboxylate (597 mg) were added
thereto, followed by stirring at room temperature for 1 hour.
Furthermore, EDCI (750 mg), 1-hydroxy-7-azabenzotriazole (532 mg),
triethylamine (1.28 mL), and tert-butylhydrazinecarboxylate (597
mg) were added thereto, followed by stirring at an oil bath
temperature of 60.degree. C. for 1 hour. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate, washed with
water, 1 M hydrochloric acid, and a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=7:3 to 3:7) to obtain tert-butyl
2-[(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazi-
n-2-yl)carbonyl]hydrazinecarboxylate (710 mg) as a white amorphous
substance.
Preparation Example 28
[0199] tert-Butyl
2-[(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazi-
n-2-yl)carbonyl]hydrazinecarboxylate (705 mg) and ethyl acetate (15
mL) were mixed, and a 4 M hydrogen chloride/ethyl acetate solution
(7 mL) was added thereto, followed by stirring for 30 minutes. The
reaction mixture was concentrated under reduced pressure, and
dichloromethane (15 mL) and trifluoroacetic acid (3.17 mL) were
added thereto, followed by stirring for 1 hour. Further,
trifluoroacetic acid (2 mL) was added thereto, followed by stirring
for 2 hours. To the reaction mixture was added toluene, followed by
concentration under reduced pressure. The residue was diluted with
ethyl acetate, and water and a saturated aqueous sodium hydrogen
carbonate solution were added thereto to carry out liquid
separation. The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The obtained
residue was purified by silica gel column chromatography (ethyl
acetate:methanol=1:0 to 19:1) to obtain
3-{[5-(hydrazinocarbonyl)pyrazin-2-yl]oxy}-5-isopropoxy-N-(1-methyl-1H-py-
razol-3-yl)benzamide (397 mg) as a white solid.
Preparation Example 29
[0200] Ethyl
5-[3-isopropoxy-5-(1H-pyrazol-3-ylcarbamoyl)phenoxy]pyridine-2-carboxylat-
e (941 mg), methanol (20 mL), and a 5 M aqueous sodium hydroxide
solution (1.4 mL) were mixed, followed by stirring at 60.degree. C.
for 2 hours and adjusting to pH 4 by the addition of 1 M
hydrochloric acid under ice-cooling. Water (80 mL) was added
thereto, and the precipitated solid was collected by filtration
while washing with a solvent (methanol:water=5:1) to obtain
5-[3-isopropoxy-5-(1H-pyrazol-3-ylcarbamoyl)phenoxy]pyridine-2-carboxylic
acid (763 mg) as a white solid.
Preparation Example 30
[0201]
5-[3-Isopropoxy-5-(1H-pyrazol-3-ylcarbamoyl)phenoxy]pyridine-2-carb-
oxylic acid (763 mg) and DMF (20 mL) were mixed, and EDCI (580 mg),
1-hydroxy-7-azabenzotriazole (413 mg), ethyl
(2E)-amino(hydroxyimino)acetate (352 mg), and triethylamine (0.84
mL) were added thereto, followed by stirring at room temperature
for 3 days. To the reaction mixture was added water, followed by
extraction with ethyl acetate.
[0202] The organic layer was washed with water and saturated brine,
and dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. To the obtained residue were
added dioxane (50 mL) and pyridinium p-toluenesulfonate (50 mg),
followed by heating to reflux for 24 hours. The reaction mixture
was cooled to room temperature, and water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with water, a saturated aqueous sodium hydrogen carbonate
solution, and saturated brine, and dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
obtained residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1 to 1:3) to obtain ethyl
5-{5-[3-isopropoxy-5-(1H-pyrazol-3-ylcarbamoyl)phenoxy]pyridin-2-yl}-1,2,-
4-oxadiazole-3-carboxylate (670 mg) as a white amorphous
substance.
Preparation Example 31
[0203] 5-Fluoropyridine-2-carboxylic acid (2.846 g) and DMF (30 mL)
were mixed, and EDCI (4.98 g), 1-hydroxy-7-azabenzotriazole (3.53
g), tert-butyl hydrazinecarboxylate (3.73 g), and triethylamine
(7.9 mL) were added thereto, followed by stirring at room
temperature overnight. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous sodium hydrogen carbonate solution
and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure and the obtained
crude product was purified by silica gel column chromatography
(hexane:ethyl acetate=2:1 to 1:1) to obtain tert-butyl
2-[(5-fluoropyridin-2-yl)carbonyl]hydrazinecarboxylate (3.372 g) as
a white solid.
Preparation Example 32
[0204] To a solution of tert-butyl
2-[(5-fluoropyridin-2-yl)carbonyl]hydrazinecarboxylate (3.37 g) in
dichloromethane (40 mL) was added trifluoroacetic acid (20 mL),
followed by stirring at room temperature for 2 hours. The reaction
mixture was concentrated under reduced pressure and adjusted to
pH=8 by the addition of a saturated aqueous sodium hydrogen
carbonate solution, and then saturated brine was added thereto,
followed by extraction with solvent (chloroform:isopropyl
alcohol=4:1) four times. The organic layer was dried over anhydrous
magnesium sulfate and the solvent was evaporated under reduced
pressure to obtain 5-fluoropyridine-2-carbohydrazide (1.88 g) as a
light yellow solid.
Preparation Example 33
[0205] Into a solution of 5-fluoropyridine-2-carbohydrazide (1 g)
in dichloromethane (30 mL) was mixed triethylamine (2.7 mL), and
methyl chloroglyoxylate (0.59 mL) was added thereto under
ice-cooling, followed by stirring at room temperature for 5 hours.
p-Toluenesulfonyl chloride (1.23 g) was added thereto under
ice-cooling, followed by stirring at room temperature overnight. To
the reaction mixture was added water at room temperature to carry
out liquid separation, and the organic layer was concentrated.
After concentration, the obtained oily substance was dissolved in
ethyl acetate. Together with the aqueous layer, liquid separation
was carried out. The organic layer was washed with a saturated
aqueous sodium hydrogen carbonate solution and saturated brine. The
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. The obtained solid was collected by filtration
while washing with a solvent (hexane:ethyl acetate=4:1) to obtain
methyl 5-(5-fluoropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate
(1.073 g) as a gray solid.
Preparation Example 34
[0206] To a suspension of methyl
5-(5-fluoropyridin-2-yl)-1,3,4-oxadiazole-2-carboxylate (1.07 g) in
THF (5 mL) was added a 2 M methylamine/THF solution (7.2 mL) at
room temperature, followed by stirring at room temperature for 2
hours. After concentration, the obtained solid was collected by
filtration while washing with a solvent (hexane:ethyl acetate=1:1)
to obtain
5-(5-fluoropyridin-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide
(968 mg) as an orange solid.
Preparation Example 35
[0207] To a solution of methyl
3-(4-aminophenoxy)-5-isopropoxybenzoate (1.3 g) in dichloroethane
(25 mL) were sequentially added cyclopropane carboxaldehyde (302
mg) and sodium triacetoxyborohydride (1.0 g), followed by stirring
at room temperature for 2 hours. Then, to the reaction mixture was
added an aqueous sodium hydrogen carbonate solution, followed by
alkalifying by the addition of sodium hydrogen carbonate. The
organic layer was washed with saturated brine and then dried over
anhydrous magnesium sulfate. After concentration, the obtained
residue was purified by silica gel column chromatography (0 to 10%
ethyl acetate/hexane) to obtain methyl
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoate (1.53
g) as a light brown oil.
Preparation Example 36
[0208] To a solution of methyl
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoate (1.3
g) in dichloromethane (10 mL) were added pyridine (0.5 mL) and
acetic anhydride (0.6 mL), followed by stirring at room temperature
for 1 hour. After concentration, the residue was dissolved in ethyl
acetate, and the organic layer was washed with 1 M hydrochloric
acid, a saturated aqueous sodium hydrogen carbonate solution, and
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate and then concentrated, and the residue was
purified by silica gel column chromatography (0 to 50% ethyl
acetate/hexane) to obtain methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoate
(1.15 g) as a colorless oil.
Preparation Example 37
[0209] To a solution of methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoate
(212 mg) in methanol (5 mL) was added a 1 M aqueous sodium
hydroxide solution (0.8 mL), followed by stirring at room
temperature overnight. After concentration under reduced pressure,
water (10 mL), 1 M hydrochloric acid (1.9 mL), and ethyl acetate
(20 mL) were added thereto, and the organic layer was washed with
saturated brine (20 mL) and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoic
acid (170 mg) as a colorless amorphous substance.
Preparation Example 38
[0210] To a solution of methyl 3,5-dihydroxybenzoate (50 g) in DMF
(1 L) was added potassium tert-butoxide (70 g), followed by
stirring at room temperature for 30 minutes. A solution of
1-fluoro-4-nitrobenzene (30 mL) in DMF (30 mL) was added dropwise
thereto under ice-cooling. After leaving to stand at room
temperature overnight, 1 M hydrochloric acid (500 mL) was added
thereto under ice-cooling. Water (3 L) was added thereto, followed
by extraction with ethyl acetate (500 mL, twice). The organic layer
was washed with a saturated aqueous sodium hydrogen carbonate
solution (1 L) and saturated brine (500 mL), and dried over
anhydrous magnesium sulfate, and the solvent was then evaporated
under reduced pressure. To the residue was added a solvent (500 mL,
hexane:ethyl acetate=2:1), and the precipitate was collected by
filtration and dried to obtain methyl
3-hydroxy-5-(4-nitrophenoxy)benzoate (57.87 g) as a light yellow
solid.
Preparation Example 39
[0211] To a solution of {1-[(benzyloxy)methyl]cyclobutyl}methanol
(3 g), methyl 3-hydroxy-5-(4-nitrophenoxy)benzoate (5.05 g), and
tributylphosphine (4.3 mL) in THF (60 mL) was added
1,1'-(azodicarbonyl)dipiperidine (4.40 g) under ice-cooling,
followed by stirring at room temperature for 5 hours and at
60.degree. C. overnight. After leaving to stand for cooling at room
temperature, the precipitated solid was collected by filtration
while washing with a solvent (hexane:ethyl acetate=1:1). The
filtrate was concentrated and the obtained oily substance was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:0 to 5:1) to obtain methyl
3-({1-[(benzyloxy)methyl]cyclobutyl}methoxy)-5-(4-nitrophenoxy)benzoate
(4.07 g) as a light yellow oily substance.
Preparation Example 40
[0212] To a mixed solution of methyl
3-({1-[(benzyloxy)methyl]cyclobutyl}methoxy)-5-(4-nitrophenoxy)benzoate
(4.07 g) in methanol (120 mL) and water (40 mL) were added reduced
iron (4.77 g) and ammonium chloride (913 mg) at room temperature,
followed by stirring at 80.degree. C. for 4 hours. After leaving to
stand for cooling at room temperature and filtering using Celite,
the filtrate was extracted with ethyl acetate. The organic layer
was washed with a saturated aqueous sodium hydrogen carbonate
solution and saturated brine, dried over anhydrous magnesium
sulfate, and concentrated to obtain methyl
3-(4-aminophenoxy)-5-({1-[(benzyloxy)methyl]cyclobutyl}methoxy)benzoate
(3.891 g) as a light yellow oily substance.
Preparation Example 41
[0213] A mixture of methyl
3-(4-acetamidephenoxy)-5-isopropoxybenzoate (150 mg),
1-fluoro-2-iodoethane (152 mg), potassium carbonate (121 mg), and
DMF (2 mL) was stirred at 60.degree. C. for 1 hour. 60% sodium
hydride (17 mg) was added thereto, followed by stirring at
80.degree. C. for 4 days. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. The solvent was evaporated and the obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=50:50) to obtain methyl
3-{4-[acetyl(2-fluoroethyl)amino]phenoxy}-5-isopropoxybenzoate (100
mg) as a light yellow amorphous substance.
Preparation Example 42
[0214] A mixture of methyl 3-(4-aminophenoxy)-5-isopropoxybenzoate
(2 g), di-tert-butyldicarbonate (1.59 g), triethylamine (1.02 mL),
and DMF (20 mL) was stirred at room temperature for 3 hours. To the
reaction mixture was added water, followed by extraction with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate, and the solvent was
evaporated. To the obtained residue were added ethyl
acetate/hexane, and the precipitated solid was collected by
filtration to obtain methyl
3-{4-[(tert-butoxycarbonyl)amino]phenoxy}-5-isopropoxybenzoate (2.3
g) as a white solid.
Preparation Example 43
[0215] A mixture of methyl
3-{4-[(tert-butoxycarbonyl)amino]phenoxy}-5-isopropoxybenzoate (1.2
g), (bromomethyl)cyclopropane (484 mg), 60% sodium hydride (132
mg), and DMF (10 mL) was stirred at room temperature for 5 hours.
To the reaction mixture was added water, followed by extraction
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate, and the solvent was
evaporated. The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=20:80 to 50:50) to obtain
methyl
3-{4-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]phenoxy}-5-isopropoxy-
benzoate (1.3 g) as a white solid.
Preparation Example 44
[0216] To a solution of methyl 3-hydroxy-5-(4-nitrophenoxy)benzoate
(5.4 g) in DMF (60 mL) were added potassium carbonate (7.2 g) and
benzyl 1-bromocyclobutane carboxylate (10 g), followed by stirring
at an internal temperature of 70.degree. C. for 3 hours. Then,
benzyl 1-bromocyclobutane carboxylate (5 g) was added thereto,
followed by stirring for 2 hours. Benzyl 1-bromocyclobutane
carboxylate (2.3 g) was added thereto again, followed by stirring
overnight. After leaving to stand for cooling at room temperature,
water (200 mL) and ethyl acetate (200 mL) were added thereto, and
the organic layer was washed with water (200 mL), a saturated
aqueous sodium hydrogen carbonate solution (200 mL), 1 M
hydrochloric acid (200 mL), and saturated brine (200 mL), and dried
over anhydrous magnesium sulfate. Then, the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate=95/5.fwdarw.80/20) to
obtain methyl
3-({1-[(benzyloxy)carbonyl]cyclobutyl}oxy)-5-(4-nitrophenoxy)benzoate
(8.38 g) as a yellow oily substance.
Preparation Example 45
[0217] Methyl 3-(4-aminophenoxy)-5-(benzyloxy)benzoate (6.87 g) and
dichloroethane (70 mL) were mixed, and cyclopropane carboxaldehyde
(2.07 mL) and acetic acid (7.0 mL) were added thereto, followed by
stirring at room temperature for 30 minutes. Sodium
triacetoxyborohydride (6.18 g) was added thereto under ice-cooling,
followed by stirring for 30 minutes. To the reaction mixture was
added water, followed by extraction with chloroform. The organic
layer was washed with water, a saturated aqueous sodium hydrogen
carbonate solution, and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure.
[0218] The obtained oily substance and dichloromethane (70 mL) were
mixed, and pyridine (4.77 mL) and acetic anhydride (5.58 mL) were
added thereto, followed by stirring for 1 hour. The reaction
mixture was concentrated under reduced pressure, diluted with ethyl
acetate, washed with water and a saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, filtered, and
concentrated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=4:1 to 2:1) to obtain methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-(benzyloxy)benzoate
(5.31 g) as a brown oily substance.
Preparation Example 46
[0219] To a solution of methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-({1-[(benzyloxy)carbonyl]-
cyclobutyl}oxy)benzoate (2.75 g) in ethyl acetate (5 mL) and
methanol (15 mL) was added 10% palladium/carbon (200 mg), followed
by stirring at room temperature for 2 hours under a hydrogen
atmosphere of 0.3 MPa. The precipitate was removed using Celite and
the filtrate was concentrated under reduced pressure to obtain
1-[3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-(methoxycarbonyl)pheno-
xy]cyclobutane carboxylic acid (2.09 g) as a colorless amorphous
substance.
Preparation Example 47
[0220] To a solution of
1-[3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-(methoxycarbonyl)pheno-
xy]cyclobutane carboxylic acid (2.09 g) in THF (30 mL) were added
triethylamine (0.77 mL) and isobutylchlorocarbonate (0.71 mL) under
ice-cooling, followed by stirring for 1 hour under ice-cooling, and
then the precipitate was separated by filtration. To the filtrate
were added sodium borohydride (470 mg) and methanol (3 mL),
followed by stirring at room temperature for 1 hour, and then ice
and 1 M hydrochloric acid (30 mL) were added thereto. After
concentration under reduced pressure, ethyl acetate (200 mL) and
water (100 mL) were added thereto, and the organic layer was washed
sequentially with a saturated aqueous sodium hydrogen carbonate
solution (100 mL) and saturated brine (100 mL), and dried over
anhydrous magnesium sulfate. Then, the solvent was evaporated under
reduced pressure and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate=30/70.fwdarw.10/90) to obtain
methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-{[1-(hydroxymethyl)cyclob-
utyl]oxy}benzoate (1.02 g) as a colorless oil.
Preparation Example 48
[0221] To a solution of methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-{[1-(hydroxymethyl)cyclob-
utyl]oxy}benzoate (1.02 g) in DMF (10 mL) were added imidazole (365
mg) and tert-butyl (chloro)dimethylsilane (770 mg), followed by
stirring at room temperature overnight. Water (40 mL) and ethyl
acetate (40 mL) were added thereto, and the organic layer was
washed sequentially with a saturated aqueous sodium hydrogen
carbonate solution (30 mL), 1 M hydrochloric acid (30 mL), and
saturated brine (30 mL), and dried over anhydrous magnesium
sulfate. Then, the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=80/20.fwdarw.50/50) to obtain methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-{[1-([tert-butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}benzoate (1.28 g) as a
colorless oil.
Preparation Example 49
[0222] A mixture of tert-butyl
(cyclopropylmethyl){4-[3-isopropoxy-5-(1,3-thiazol-2-ylcarbamoy)phenoxy]p-
henyl}carbamate (470 mg), trifluoroacetic acid (5 mL), and
chloroform (5 mL) was stirred at room temperature for 3 hours.
After evaporation of the solvent, a saturated aqueous sodium
hydrogen carbonate solution was added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated to obtain
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-isopropoxy-N-1,3-thiazol-2-ylbe-
nzamide (380 mg) as a white amorphous substance.
Preparation Example 50
[0223] To a solution of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-methyle-
thoxy]benzoic acid (202 mg) in dichloromethane (5 mL) were added a
1 M oxalyl chloride/dichloromethane solution (0.54 mL) and DMF (3
droplets) under ice-cooling, followed by stirring at room
temperature for 60 minutes. tert-Butyl
3-amino-1H-pyrazole-1-carboxylate (107 mg) and pyridine (0.08 mL)
were added thereto under ice-cooling, followed by stirring at room
temperature overnight. Water was added thereto, followed by
extraction with ethyl acetate, and the organic layer was washed
with a saturated aqueous ammonium chloride solution, a saturated
aqueous sodium hydrogen carbonate solution, and saturated brine,
and dried over anhydrous magnesium sulfate. Then, the solvent was
evaporated under reduced pressure and the obtained crude product
was purified by silica gel column chromatography (hexane:ethyl
acetate=2:1 to 1:2) to obtain tert-butyl
3-[(3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-met-
hylethoxy]benzoyl)amino]-1H-pyrazole-1-carboxylate (181 mg) as a
white amorphous substance.
Preparation Example 51
[0224] To a solution of methyl
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-
benzoate (1.263 g) in dichloromethane (20 mL) were added
triethylamine (1.4 mL) and methanesulfonyl chloride (0.28 mL) under
ice-cooling, followed by stirring for 2 hours under ice-cooling.
Water was added thereto, followed by extraction with ethyl acetate.
The organic layer was washed with 1 M hydrochloric acid, a
saturated aqueous sodium hydrogen carbonate solution, and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated to
obtain methyl
3-{4-[(cyclopropylmethyl)(methylsulfonyl)amino]phenoxy}-5-[(1S)-2-methoxy-
-1-methylethoxy]benzoate (1.795 g) as a yellow oily substance.
Preparation Example 52
[0225] To a solution of methyl
3-(2-chloro-4-nitrophenoxy)-5-hydroxybenzoate (2.5 g) in DMF (25
mL) were added potassium carbonate (2.51 g) and 2-iodopropane (1.0
mL) at room temperature, followed by stirring 50.degree. C. for 5
hours. 2-Iodopropane (1.0 mL) was added thereto again, followed by
stirring at 50.degree. C. for 4 hours. After leaving to stand for
cooling to room temperature, water was added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated to
obtain methyl 3-(2-chloro-4-nitrophenoxy)-5-isopropoxybenzoate
(3.135 g) as a yellow oily substance.
Preparation Example 53
[0226] A mixture of tert-butyl
5-[3-isopropoxy-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylate
(0.7 g), trifluoroacetic acid (3 mL), and chloroform (3 mL) was
stirred at room temperature for 2 hours. The solvent was evaporated
and water was added thereto, followed by extraction with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate, and the solvent was
evaporated. The residue was solidified with dichloromethane/diethyl
ether/hexane to obtain
5-[3-isopropoxy-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylic
acid (0.4 g) as a white solid.
Preparation Example 54
[0227] A mixture of
5-[3-isopropoxy-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylic
acid (3.6 g), diphenyl phosphoryl azide (3.49 mL), triethylamine
(3.02 mL), and tert-butanol (36 mL) was heated to reflux for 1
hour. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=10:90) to obtain
methyl
3-({5-[(tert-butoxycarbonyl)amino]pyrazin-2-yl}oxy)-5-isopropoxybenzoate
(2.5 g) as a light yellow oily substance.
Preparation Example 55
[0228] A mixture of methyl
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropoxybenzoate
(0.5 g), acetic anhydride (5 mL), and 4-dimethylaminopyridine (1.03
g) was stirred at 80.degree. C. overnight. To the reaction mixture
was added water, followed by extraction with ethyl acetate. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate, and the solvent was evaporated. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=20:80 to 50:50) to obtain methyl
3-({5-[acetyl(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropo-
xybenzoate (347 mg) as a light yellow oily substance.
Preparation Example 56
[0229] A mixture of methyl
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropoxybenzoate
(0.2 g), 2-methylpropanoyl chloride (0.45 mL), and
4-dimethylaminopyridine (1.51 g) was stirred at room temperature
for 3 hours. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=20:80) to obtain
methyl
3-({5-[(cyclopropylmethyl)(isobutyryl)amino]pyrazin-2-yl}oxy)-5-isopropox-
ybenzoate (0.2 g) as a light yellow oil.
Preparation Example 57
[0230] A mixture of
3-({5-[(cyclopropylmethyl)(isobutyryl)amino]pyrazin-2-yl}oxy)-5-isopropox-
ybenzoic acid (120 mg), tert-butyl
3-amino-1H-pyrazole-1-carboxylate (160 mg),
N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylen-
e]-N-methylmethaneaminium hexafluorophosphate (221 mg),
triethylamine (0.11 mL), DMF (0.5 mL), and 4-dimethylaminopyridine
(35 mg) was stirred at 50.degree. C. overnight. To the reaction
mixture was added water, followed by extraction with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate, and the solvent was evaporated. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=20:80) to obtain tert-butyl
3-{[3-({5-[cyclopropylmethyl)(isobutyryl)amino]pyrazin-2-yl}oxy)-5-isopro-
poxybenzoyl]amino}-1H-pyrazole-1-carboxylate (80 mg) as a white
solid.
Preparation Example 58
[0231] Methyl 3-hydroxy-5-(4-nitrophenoxy)benzoate (20.0 g),
potassium carbonate (10.5 g), and DMF (200 mL) were mixed, and
(bromomethyl)benzene (9.10 mL) was added thereto, followed by
stirring at room temperature for 8 hours. The solid was removed by
filtration and water was added thereto, followed by extraction with
ethyl acetate. The organic layer was washed with water and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1 to 4:1) to obtain
methyl 3-(benzyloxy)-5-(4-nitrophenoxy)benzoate (26.0 g) as a
yellow solid.
Preparation Example 59
[0232] Methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-(benzyloxy)benzoate
(5.31 g) and trifluoroacetic acid (60 mL) were mixed, and
1,2,3,4,5-pentamethylbenzene (8.84 g) was added thereto under
ice-cooling, followed by warming to room temperature and stirring
for 5 hours. To the reaction mixture was added toluene, followed by
concentration under reduced pressure. The obtained residue was
diluted with ethyl acetate, and washed with water, and a saturated
aqueous sodium chloride solution. The organic layer was dried over
anhydrous magnesium sulfate and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=9:1 to 1:1) to obtain
methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-hydroxybenzoate
(3.34 g) as a white solid.
Preparation Example 60
[0233] Methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-hydroxybenzoate
(500 mg), potassium carbonate (292 mg), chloromethyl
(methyl)sulfide (0.175 mL), and DMF (5 mL) were mixed, followed by
stirring at an oil bath temperature of 60.degree. C. for 2 hours
and further stirring at an oil bath temperature of 80.degree. C.
for 1 hour. Further, potassium carbonate (292 mg) and
chloromethyl(methyl)sulfide (0.175 mL) were added thereto, followed
by stirring at an oil bath temperature of 80.degree. C. for 1 hour.
The reaction mixture was cooled to room temperature, and water was
added thereto, followed by extraction with ethyl acetate. The
organic layer was washed with water and a saturated aqueous sodium
chloride solution, and dried over anhydrous magnesium sulfate, and
the solvent was evaporated under reduced pressure. The obtained
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=9:1 to 4:1).
[0234] The obtained oily substance and dichloromethane (10 mL) were
mixed, and metachloroperbenzoic acid (75%, 1.30 g) was added
thereto under ice-cooling, followed by stirring at room temperature
for 2 hours. To the reaction mixture was added an aqueous sodium
sulfite solution, followed by extraction with ethyl acetate. The
organic layer was washed with water, a 1 M aqueous sodium hydroxide
solution, and a saturated aqueous sodium chloride solution, and
dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1 to 0:1) to obtain methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(methylsulfonyl)methoxy]-
benzoate (489 mg) as a colorless oily substance.
Preparation Example 61
[0235] Methyl
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-hydroxybenzoate
(300 mg), potassium carbonate (175 mg), bromoacetonitrile (152 mg),
and DMF (3 mL) were mixed, followed by stirring at an oil bath
temperature of 60.degree. C. for 1 hour. The reaction mixture was
cooled to room temperature, and water was added thereto, followed
by extraction with ethyl acetate. The organic layer was washed with
water and a saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (hexane:ethyl acetate=9:1 to 0:1). The
obtained residue and methanol (6 mL) were mixed, and a 1 M aqueous
sodium hydroxide solution (1.01 mL) was added thereto, followed by
stirring at room temperature for 1 hour and leaving to stand for 3
days. The reaction mixture was concentrated under reduced pressure,
and water and 1 M hydrochloric acid were added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
water and a saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The obtained residue was purified by silica
gel column chromatography (chloroform:methanol=10:0 to 19:1) to
obtain an oily substance.
[0236] The obtained oily substance and 1-methyl-1H-pyrazole-3-amine
(164 mg), EDCI (243 mg), HOBt (171 mg), and DMF (6 mL) were mixed,
followed by stirring at an oil bath temperature of 60.degree. C.
for 1 hour. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
water, 1 M hydrochloric acid, a 1 M aqueous sodium hydroxide
solution, and a saturated aqueous sodium chloride solution, and
dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1 to 0:1).
[0237] The obtained residue and methanol (6 mL) were mixed, and a 1
M aqueous sodium hydroxide solution (1.01 mL) was added thereto,
followed by leaving to stand at room temperature for 30 minutes.
The reaction mixture was concentrated under reduced pressure, and
water and 1 M hydrochloric acid were added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
water and a saturated aqueous sodium chloride solution, and dried
over anhydrous magnesium sulfate, and the solvent was evaporated
under reduced pressure. The obtained solid was washed with ethyl
acetate and filtered to obtain
(3-}4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1-methyl-1H-pyrazol-3--
yl)carbamoyl]phenoxy)acetic acid (103 mg) as a white solid.
Preparation Example 62
[0238] To a solution of methyl 3-bromo-5-hydroxybenzoate (11.1 g)
in DMF (100 mL) were added potassium carbonate (9.96 g) and
tert-butyl 5-chloropyrazine 2-carboxylate (10.8 g) at room
temperature, followed by stirring at 60.degree. C. for 2 hours.
After returning to room temperature, water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and concentrated to obtain a yellow oily substance (23.53
g). To a solution of the obtained oily substance in dichloromethane
(100 mL) was added trifluoroacetic acid (100 mL) at room
temperature, followed by stirring at room temperature for 3 hours.
After concentration, the obtained solid was collected by filtration
while washing with a solvent (hexane:ethyl acetate=1:1) to obtain
5-[3-bromo-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylic acid
(14.98 g) as a white solid.
Preparation Example 63
[0239] To a solution of methyl
3-bromo-5-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl-
}oxy)benzoate (3 g) in dichloromethane (10 mL) was added
trifluoroacetic acid (10 mL) at room temperature, followed by
stirring at room temperature for 3 hours. After concentration, a
saturated aqueous sodium hydrogen carbonate solution was added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. To a
solution of the obtained residue in methanol (30 mL) was added a 4
M aqueous sodium hydroxide solution (4.7 mL), followed by stirring
at room temperature for 2 hours. 1 M hydrochloric acid was added
thereto at room temperature to adjust the pH to 4, and water (150
mL) was added thereto. The obtained solid was collected by
filtration while washing with a solvent (water:methanol=5:1) to
obtain
3-bromo-5-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)benzoic
acid (2.22 g) as a light yellow solid.
Preparation Example 64
[0240] A solution of methyl
3-bromo-5-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl-
}oxy)benzoate (1.5 g), potassium carbonate (2.17 g),
trimethyboroxine (394 mg), and tetrakistriphenyl phosphine
palladium (362 mg) in 1,4-dioxane (20 mL)-water (5 mL) solution was
stirred at 110.degree. C. for 7 hours. After returning to room
temperature, water was added thereto, followed by extraction with
ethyl acetate, and the organic layer was washed with saturated
brine. The organic layer was dried over anhydrous magnesium sulfate
and concentrated. The obtained crude product was purified by silica
gel column chromatography (hexane:ethyl acetate=1:0 to 5:1) to
obtain methyl
3-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5--
methylbenzoate (1.185 g) as a white solid.
Preparation Example 65
[0241] To a solution of tert-butyl
5-[3-hydroxy-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylate
(8.87 g) in DMF (90 mL) were added potassium carbonate (4.25 g) and
benzylbromide (3.7 mL) under ice-cooling, followed by stirring at
60.degree. C. for 2 hours. Water was added thereto under
ice-cooling, followed by extraction with ethyl acetate.
[0242] The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated, and the
obtained crude product was purified by silica gel column
chromatography (hexane:ethyl acetate=10:1, 5:1, 4:1) to obtain
tert-butyl
5-[3-(benzyloxy)-5-(methoxycarbonyl)phenoxy]pyrazine-2-carboxylate
as a colorless oily substance (14.509 g, containing about 15% of
ethyl acetate in terms of ratio by weight (determined in accordance
with .sup.1H NMR)).
Preparation Example 66
[0243] A solution of methyl
3-(benzyloxy)-5-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazi-
n-2-yl}oxy)benzoate (2.1 g), 10% palladium/carbon (420 mg) in ethyl
acetate (25 mL) was stirred for 8 hours under a hydrogen atmosphere
of 0.3 MPa, and filtered using Celite, and the filtrate was
concentrated to obtain methyl
3-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5--
hydroxybenzoate (1.722 g) as a white solid.
Preparation Example 67
[0244] To a solution of methyl
3-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5--
hydroxybenzoate (753 mg) in DMF (10 mL) were added potassium
carbonate (376 mg) and ethyl iodide (0.29 mL) at room temperature,
followed by stirring 60.degree. C. for 2 hours. After leaving to
stand for cooling to room temperature, water was added thereto,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and concentrated to obtain a light yellow oily substance.
To a solution of the obtained oily substance in dichloromethane (10
mL) was added trifluoroacetic acid (2.8 mL) at room temperature,
followed by stirring at room temperature for 2 hours and
concentrating. A saturated aqueous sodium hydrogen carbonate
solution was added thereto, followed by extraction with ethyl
acetate. The organic layer was washed with saturated brine, dried
over anhydrous magnesium sulfate, and concentrated. To a mixed
solution of the obtained residue in methanol (10 mL) and
tetrahydrofuran (3 mL) was added a 4 M aqueous sodium hydroxide
solution (2.3 mL), followed by stirring at room temperature
overnight. 1 M hydrochloric acid was added thereto at room
temperature to adjust the pH to 4, and saturated brine was added
thereto, followed by extraction with chloroform. The organic layer
was dried over anhydrous magnesium sulfate and concentrated to
obtain
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-ethoxybenzoic
acid (595 mg) as a light yellow amorphous substance.
Preparation Example 68
[0245] To a mixture of methyl 3-amino-5-(benzyloxy)benzoate
hydrochloride (15 g) and chloroform (150 mL) were sequentially
added cyclopropane carboxaldehyde (3 g) and sodium
triacetoxyborohydride (14 g), followed by stirring for 2 hours.
Then, to the reaction mixture was added water, the organic layer
was separated, and the obtained organic layer was washed with
water, a saturated aqueous sodium hydrogen carbonate solution, and
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate and concentrated, and the residue was then
purified by silica gel column chromatography (5-15% ethyl
acetate/hexane) to obtain methyl
3-(benzyloxy)-5-[(cyclopropylmethyl)amino]benzoate (10 g) as a
light brown oily substance.
Preparation Example 69
[0246] To methyl 3-(benzyloxy)-5-[(cyclopropylmethyl)amino]benzoate
(10 g) were added chloroform (100 mL), acetic anhydride (10 mL),
and pyridine (10 mL), followed by stirring for 3 hours. The
reaction mixture was diluted with water and ethyl acetate, and the
organic layer was washed with water, a saturated aqueous sodium
hydrogen carbonate solution, and saturated brine. The residue was
purified by silica gel column chromatography (10 to 30% ethyl
acetate/hexane) to obtain methyl
3-[acetyl(cyclopropylmethyl)amino]-5-(benzyloxy)benzoate (10.1 g)
as a colorless oily substance.
Preparation Example 70
[0247] To a solution of methyl
3-[acetyl(cyclopropylmethyl)amino]-5-(benzyloxy)benzoate (10.1 g)
in methanol (50 mL) and THF (50 mL) was added 20% palladium
hydroxide (500 mg), followed by stirring for 6 hours under a
hydrogen atmosphere of 0.5 MPa. The reaction mixture was filtered
using Celite and concentrated to obtain methyl
3-[acetyl(cyclopropylmethyl)amino]-5-hydroxybenzoate (7.3 g).
Preparation Example 71
[0248] A mixture of tetrahydro-2H-pyran-4-carboxylic acid (200 mg),
oxalyl chloride (0.13 mL), DMF (0.010 mL), and dichloromethane
(0.85 mL) was stirred at room temperature for 2 hours. To the
reaction mixture were added methyl
3-[acetyl(cyclopropylmethyl)amino]-5-({5-[(cyclopropylmethyl)amino]pyrazi-
n-2-yl}oxy)benzoate (170 mg) and 4-dimethylaminopyridine (101 mg),
followed by stirring at room temperature for 4 hours. To the
reaction mixture was added hydrochloric acid, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate. The
solvent was evaporated and the obtained residue was purified by
silica gel column chromatography (ethyl acetate:hexane=20:80) to
obtain a light yellow oily substance. A mixture of the obtained
oily substance, a 1 M aqueous sodium hydroxide solution (1 mL),
methanol (1 mL), and tetrahydrofuran (1 mL) was stirred at room
temperature for 2 hours. To the reaction mixture was added 1 M
hydrochloric acid to adjust the pH to 4, followed by extraction
with ethyl acetate. The organic layer was washed with saturated
brine, and dried over anhydrous sodium sulfate. The solvent was
evaporated to obtain
3-[acetyl(cyclopropylmethyl)amino]-5-({5-[(cyclopropylmethyl)(tetrahydro--
2H-pyran-4-ylcarbonyl)amino]pyrazin-2-yl}oxy)benzoic acid (175 mg)
as a white amorphous substance.
Preparation Example 72
[0249] To a solution of methyl
3-(4-aminophenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]benzoate (6.22
g) in dichloroethane (70 mL) were added cyclopropane carboxaldehyde
(2.0 mL) and acetic acid (6.7 mL) at room temperature, followed by
stirring at room temperature for 30 minutes. Sodium
triacetoxyborohydride (5.89 g) was added thereto, followed by
stirring at room temperature overnight. Water was added thereto at
room temperature, followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous sodium hydrogen
carbonate solution and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to
obtain a light yellow oily substance. To a solution of
tetrahydro-2H-pyran-4-carboxylic acid (2.44 g) in dichloromethane
(50 mL) were added oxalyl chloride (1.66 mL) and DMF (3 droplets)
under ice-cooling, followed by stirring at room temperature for 2
hours. Then, a solution of the previously obtained light yellow
oily substance in dichloromethane (30 mL) and pyridine (3 mL) was
added thereto under ice-cooling, followed by stirring at room
temperature for 2 hours. Water was added thereto under ice-cooling,
followed by extraction with ethyl acetate. The organic layer was
washed with 1 M hydrochloric acid, a saturated aqueous sodium
hydrogen carbonate solution, and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained oily substance was purified by silica gel
column chromatography (hexane:ethyl acetate=3:1 to 1:2) to obtain
methyl
3-{4-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]phenoxy}-
-5-{[(2S)-1-methoxypropan-2-yl]oxy}benzoate (5.526 g) as a pink
oily substance.
Preparation Example 73
[0250] A mixture of tetrahydro-2H-pyran-4-carboxylic acid (328 mg),
oxalyl chloride (0.22 mL), DMF (0.019 mL), and dichloromethane (2
mL) was stirred at room temperature for 2 hours. To the reaction
mixture were added methyl
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropoxybenzoate
(180 mg) and 4-dimethylaminopyridine (123 mg), followed by stirring
at 50.degree. C. overnight. To the reaction mixture was added
water, followed by extraction with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=40:60) to obtain methyl
3-({5-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyrazin-
-2-yl}oxy)-5-isopropoxybenzoate (165 mg) as a light yellow oily
substance.
Preparation Example 74
[0251] A mixture of
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-[(2S)-1-methoxypropan-
-2-yl]oxy}benzoic acid (1.9 g), 1-methyl-1H-pyrazole-3-amine (988
mg), EDCI (1.46 g), HOBt (1.03 g), and DMF (10 mL) was stirred at
room temperature overnight. To the reaction mixture was added
water, followed by extraction with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:chloroform=70:30) to obtain
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-{[(2S)-1-methoxypropa-
n-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.4 g) as a
light yellow amorphous substance.
Preparation Example 75
[0252] A mixture of methyl
3-({5-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyrazin-
-2-yl}oxy)-5-{[(2S)-1-methoxypropan-2-yl]oxy}benzoate (180 mg), a 1
M aqueous sodium hydroxide solution (2 mL), ethanol (2 mL),
2-propanol (2 mL), and tetrahydrofuran (2 mL) was stirred at room
temperature for 20 minutes. To the reaction mixture was added 1 M
hydrochloric acid to adjust the pH to 4, followed by extraction
with chloroform. The organic layer was washed with saturated brine
and dried over anhydrous sodium sulfate, and the solvent was
evaporated to obtain a white amorphous substance. A mixture of this
amorphous substance, tert-butyl 3-amino-1H-pyrazole-1-carboxylate
(66 mg),
N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N--
methylmethaneamminium hexafluorophosphate (137 mg), DMF (0.5 mL),
and 4-dimethylaminopyridine (44 mg) was stirred at 50.degree. C.
overnight. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=50:50) to obtain
tert-butyl
3-{[3-({5-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyr-
azin-2-yl}oxy)-5-{[(2S)-1-methoxypropan-2-yl]oxy}benzoyl]amino}-1H-pyrazol-
e-1-carboxylate (200 mg) as a white amorphous substance.
Preparation Example 76
[0253] To a mixture of tert-butyl
5-[3-isopropoxy-5-(methoxycarbonyl)phenoxy]pyridine-2-carboxylate
(1.05 g), and chloroform (4 mL) was added trifluoroacetic acid (4
mL), followed by stirring at 50.degree. C. for 4 hours. After
leaving to stand for cooling to room temperature, the solvent was
evaporated under reduced pressure and azeotroped with toluene to
obtain a light yellow oily substance. To the obtained oily
substance were added tert-butanol (15 mL), triethylamine (0.58 mL),
and diphenyl phosphoryl azide (0.73 mL), followed by stirring at
90.degree. C. for 5 hours. After leaving to stand for cooling to
room temperature, to the reaction mixture was added water, followed
by extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate, and the
solvent was then evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=80/20) to obtain methyl
3-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}oxy)-5-isopropoxybenzoate
(350 mg) as a colorless solid.
Preparation Example 77
[0254] To a solution of methyl
3-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}oxy)-5-isopropoxybenzoate
(312 mg) in dimethylformamide (5 mL) was added 60% sodium hydride
(210 mg), followed by stirring at room temperature for 15 minutes.
To the reaction mixture was added (bromomethyl)cyclopropane (0.3
mL), followed by stirring at the same temperature for 2 hours. To
the reaction mixture was added a 10% aqueous citric acid solution,
followed by extraction with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane/ethyl acetate=6/4-3/7) to obtain
3-({6-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyridin-3-yl}oxy)-5--
isopropoxybenzoic acid (269 mg) as a colorless amorphous
substance.
Preparation Example 78
[0255] A mixture of methyl
3-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5--
hydroxybenzoate (200 mg), sodium chlorodifluoroacetate (184 mg),
cesium carbonate (235 mg), and DMF (2 mL) was stirred at
100.degree. C. overnight. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=10:90) to obtain methyl
3-({5-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5--
(difluoromethoxy)benzoate (100 mg) as a light yellow oil.
Preparation Example 79
[0256]
3-{[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-5-hyd-
roxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (490 mg), ethyl
5-fluoropyridine-2-carboxylate (231 mg), potassium carbonate (377
mg), and DMF (10 mL) were mixed, followed by stirring at an oil
bath temperature of 80.degree. C. for 1 hour and then stirring at
an oil bath temperature of 120.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
washed with water and a saturated aqueous sodium chloride solution,
and dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure.
[0257] The obtained residue and THF (10 mL) were mixed, and
tetrabutylammonium fluoride (1 M THF solution; 1.14 mL) was added
thereto, followed by stirring at room temperature for 1 hour,
diluting with ethyl acetate, washing with water and then washing
with a saturated aqueous sodium chloride solution, and drying over
anhydrous magnesium sulfate. Then solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1 to 0:1) to obtain
ethyl
5-(3-{[1-(hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)carb-
amoyl]phenoxy)pyridine-2-carboxylate (419 mg) as a white amorphous
substance.
[0258] The Preparation Example Compounds 80 to 193 were prepared in
the same manner as the methods of Preparation Examples 1 to 79. For
the Preparation Example
[0259] Compounds, the structures are shown in Tables 4 to 50 below,
and the preparation methods and the physicochemical data are shown
in Tables 96 to 101.
Example 1
[0260] To a solution of ethyl
5-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxylate (320
mg) in THF (4 mL) were added a 28% aqueous ammonia solution (1 mL)
and methanol (0.6 mL), followed by stirring for 0.5 hours. The
solid collected by filtration after concentration and then dilution
with water was washed with ethyl acetate to obtain
5-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-3-carboxamide (260
mg) as a colorless solid.
Example 2
[0261] Ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxylate (100 mg), ethanol (3 mL), and
a 2 M methylamine/THF solution (1.01 mL) were mixed, stirred at
room temperature for 1 hour, and left to stand overnight. The
reaction mixture was concentrated under reduced pressure and
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1 to 0:1). The obtained residue was dissolved in ethyl
acetate, added dropwise to hexane, and concentrated under reduced
pressure. The obtained solid was washed with diisopropyl ether and
collected by filtration to obtain
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-N-methyl-1,2,4-oxadiazole-3-carboxamide (66 mg) as a white
solid.
Example 3
[0262] To a solution of ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,3,4-oxadiazole-2-carboxylate (1.035 g) in THF (10 mL) was
added a 2 M methylamine/THF solution (10.5 mL) at room temperature,
followed by stirring at room temperature for 2 hours. After
concentration, the obtained crude product was purified by silica
gel column chromatography (hexane:ethyl acetate=1:1 to 1:10) to
obtain a light yellow oily substance. A solution of the obtained
yellow oily substance in ethyl acetate (30 mL) was heated to
reflux, and hexane (25 mL) was added thereto, followed by leaving
to stand for cooling to room temperature and then stirring at room
temperature overnight. The precipitated solid was collected by
filtration while washing with a solvent (hexane:ethyl acetate=5:6)
to obtain
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide (774 mg) as a white
solid.
Example 4
[0263] Ethyl
3-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-5-carboxylate (270
mg), ethanol (6 mL), and cyclopropanamine (0.4 mL) were mixed,
followed by stirring at room temperature for one hour and a half.
The reaction mixture was concentrated under reduced pressure and
the obtained residue was purified by silica gel column
chromatography (70 to 100% ethyl acetate/hexane) to obtain
N-cyclopropyl-3-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-py-
razol-3-yl)carbamoyl]phenoxy)pyridin-2-yl]-1,2,4-oxadiazole-5-carboxamide
(265 mg) as a colorless solid.
Example 5
[0264] Ethyl
3-(4-{3-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}phenyl)-1,2,4-oxadia-
zole-5-carboxylate (200 mg) and NMP (4 mL) were mixed, and
azetidine hydrochloride (216 mg) and triethylamine (0.325 mL) were
added thereto, followed by stirring at an oil bath temperature of
80.degree. C. for 1 hour. Further, azetidine hydrochloride (216 mg)
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.690 mL) were added
thereto, followed by stirring at an oil bath temperature of
80.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature, and water and 1 M hydrochloric acid were added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with 1 M hydrochloric acid, water, and a saturated
aqueous sodium chloride solution, and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1 to 0:1). The obtained
solid was washed with ethyl acetate and collected by filtration to
obtain
3-{4-[5-(azetidin-1-ylcarbonyl)-1,2,4-oxadiazol-3-yl]phenoxy}-N-(1-methyl-
-1H-pyrazol-3-yl)benzamide (60 mg) as a white solid.
Example 6
[0265] Ethyl
3-(3-chloro-4-{3-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}phenyl)-1,2-
,4-oxadiazole-5-carboxylate (307 mg), ethanol (6 mL), and THF (4
mL) were mixed, and sodium borohydride (75 mg) was added thereto
under ice-cooling, followed by stirring for 15 minutes. The
reaction mixture was warmed to room temperature and stirred for 15
minutes. Sodium borohydride (75 mg) was added thereto, followed by
stirring for 15 minutes. To the reaction mixture were added water
and 1 M hydrochloric acid, followed by stirring for 15 minutes.
After extraction with ethyl acetate, the organic layer was washed
with water and a saturated aqueous sodium chloride solution, and
dried over anhydrous magnesium sulfate. Then, the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1 to 0:1). The obtained oily substance was dissolved in
ethyl acetate and added dropwise to hexane. The solvent was
evaporated under reduced pressure. The obtained solid was washed
with hexane and collected by filtration to obtain
3-{2-chloro-4-[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]phenoxy}-N-(1-methy-
l-1H-pyrazol-3-yl)benzamide (61 mg) as a white solid.
Example 7
[0266] To a solution of
3-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-N-methyl-1,2,4-oxadiazole-5-carboxamide
(230 mg) in acetonitrile (10 mL) was added iodotrimethylsilane
(0.32 mL) at room temperature. The reaction mixture was stirred at
room temperature overnight, and then a saturated aqueous sodium
hydrogen carbonate solution was added thereto under ice-cooling,
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous sodium sulfite solution and
saturated brine, and then dried over anhydrous magnesium sulfate.
After concentration, the obtained crude product was purified by
silica gel column chromatography (hexane.fwdarw.ethyl
acetate/hexane=1/1.fwdarw.chloroform.fwdarw.chloroform:methanol=10:1)
to obtain
3-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-
-yl)carbamoyl]phenoxy)pyridin-2-yl]-N-methyl-1,2,4-oxadiazole-5-carboxamid-
e (140 mg) as a colorless amorphous substance.
Example 8
[0267] Ethyl
3-(2-chloro-4-{3-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}phenyl)-1,2-
,4-oxadiazole-5-carboxylate (218 mg) and NMP (4 mL) were mixed, and
a 2 M dimethylamine/THF solution (1.17 mL) was added thereto,
followed by stirring at an oil bath temperature of 60.degree. C.
for 2 hours. The reaction mixture was cooled to room temperature,
and water was added thereto, followed by extraction with ethyl
acetate. The organic layer was washed with water and a saturated
aqueous sodium chloride solution, and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=9:1 to 0:1), and the obtained
oily substance was dissolved in ethyl acetate and added dropwise to
hexane. The solvent was evaporated under reduced pressure, and the
obtained solid was washed with diisopropyl ether and collected by
filtration to obtain
3-(2-chloro-4-{3-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}phenyl)-N,N-
-dimethyl-1,2,4-oxadiazole-5-carboxamide (39 mg) as a white
solid.
Example 9
[0268] To a solution of ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxylate (297 mg) in THF (4 mL) was
added a 28% aqueous ammonia solution (1 mL). Methanol (0.6 mL) was
added thereto, followed by stirring for 0.5 hours, concentrating,
thereafter, diluting with water, and the solid was collected by
filtration. The obtained solid was dissolved in chloroform and
methanol, and a 4 M hydrogen chloride/ethyl acetate solution (1 mL)
was added thereto. After concentration, the resulting solid was
washed with diethyl ether and methanol to obtain
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (220 mg) as a
colorless solid.
Example 10
[0269] Under a nitrogen atmosphere, to THF (3 mL) was added 2 M
dimethylamine/THF (0.765 mL), and then diisobutylaluminum hydride
(1.01 M solution in toluene, 1.40 mL) was added thereto under
ice-cooling, followed by stirring at room temperature for 1 hour.
Ethyl
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-1,2,4-oxadiazole-3-carboxylate (150 mg) was added thereto,
followed by stirring at room temperature for 2 hours. To the
reaction mixture was added an aqueous potassium hydrogen sulfate
solution, followed by extraction with ethyl acetate. The organic
layer was washed with a saturated aqueous sodium chloride solution
and dried over anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1 to 0:1). The obtained residue was dissolved in ethyl
acetate, added dropwise to hexane, and concentrated under reduced
pressure. The obtained residue was washed with hexane and collected
by filtration to obtain
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyridin-
-2-yl)-N,N-dimethyl-1,2,4-oxadiazole-3-carboxamide (47 mg) as a
white amorphous substance.
Example 11
[0270] To a mixture of
3-{[6-(N'-hydroxycarbamimidoyl)pyridin-3-yl]oxy}-5-isopropoxy-N-(1-methyl-
-1H-pyrazol-3-yl)benzamide (81 mg) and dioxane (2 mL) were
sequentially added 1,1'-carbonothioylbis(1H-imidazole) (39 mg) and
DBU (44 .mu.L) at room temperature, followed by stirring at room
temperature for 15 hours. To the reaction mixture was added 1 M
hydrochloric acid (1.2 mL), followed by addition of ethyl acetate
(15 mL) and water (15 mL) to carry out liquid separation. The
organic layer was washed with 0.1 M hydrochloric acid (15 mL) and
saturated brine (15 mL) in this order, dried over anhydrous
magnesium sulfate, and then filtered, and the filtrate was
concentrated under reduced pressure.
[0271] The residue (104 mg) was dissolved in THF (2 mL), and
triethylamine (48 .mu.L) and then iodomethane (16 .mu.L) were added
thereto under ice-cooling, followed by stirring for 30 minutes
under ice-cooling and at room temperature for 15 hours. To the
reaction mixture were added diethyl ether (15 mL) and water (15 mL)
to carry out liquid separation, and the organic layer was washed
with water (15 mL) and saturated brine (15 mL) in this order, and
dried over anhydrous magnesium sulfate. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain
3-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)-5-({6-[5-(methylsulfanyl)-1,2,4-
-oxadiazol-3-yl]pyridin-3-yl}oxy)benzamide (90 mg) as a white
amorphous substance.
Example 12
[0272]
3-({6-[3-(Hydroxymethyl)-1,2,4-oxadiazol-5-yl]pyridin-3-yl}oxy)-5-i-
sopropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (240 mg),
dichloromethane (5 mL), and triethylamine (0.180 mL) were mixed,
and methanesulfonyl chloride (0.050 mL) was added thereto under
ice-cooling, followed by stirring for 15 minutes. Further,
methanesulfonyl chloride (0.025 mL) was added thereto, followed by
stirring for 5 minutes. Further, methanesulfonyl chloride (0.025
mL) was added thereto, followed by stirring for 5 minutes. The
reaction mixture was diluted with ethyl acetate, washed with a
saturated aqueous sodium hydrogen carbonate solution, water, and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure.
[0273] The obtained residue and DMF (5 mL) were mixed, and sodium
cyanide (53 mg) was added thereto, followed by stirring at an oil
bath temperature of 50.degree. C. for 1 hour. The reaction mixture
was cooled to room temperature, diluted with ethyl acetate, washed
with a saturated aqueous sodium hydrogen carbonate solution, water,
and a saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7:3 to 2:8). The
obtained solid was washed with hexane and collected by filtration
to obtain
3-({6-[3-(cyanomethyl)-1,2,4-oxadiazol-5-yl]pyridin-3-yl}oxy)-5-isopropox-
y-N-(1-methyl-1H-pyrazol-3-yl)benzamide (103 mg) as a white
solid.
Example 13
[0274]
3-({6-[3-(Cyanomethyl)-1,2,4-oxadiazol-5-yl]pyridin-3-yl}oxy)-5-iso-
propoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (53 mg) and THF (3
mL) were mixed, and a 1 M aqueous sodium hydroxide solution (0.255
mL) was added thereto, followed by stirring at room temperature for
1 hour and stirring at an oil bath temperature of 60.degree. C. for
1 hour.
[0275] Further, a 1 M aqueous sodium hydroxide solution (0.125 mL)
was added thereto, followed by stirring for 1 hour. Further, a 1 M
aqueous sodium hydroxide solution (0.125 mL) was added thereto,
followed by stirring for 1 hour. The reaction mixture was cooled to
room temperature, and water was added thereto, followed by
extraction with ethyl acetate. The organic layer was washed with
water, a saturated aqueous ammonium chloride solution, and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:methanol=1:0 to 19:1). The
obtained residue was dissolved in ethyl acetate and added dropwise
to hexane. After concentration under reduced pressure, the
resulting solid was washed with hexane and collected by filtration
to obtain
3-({6-[3-(2-amino-2-oxoethyl)-1,2,4-oxadiazol-5-yl]pyridin-3-yl}oxy)-5-is-
opropoxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (21 mg) as a beige
solid.
Example 14
[0276] A mixture of
3-{[6-(N'-hydroxycarbamimidoyl)pyridin-3-yl]oxy}-5-isopropoxy-N-(1-methyl-
-1H-pyrazol-3-yl)benzamide (80 mg), triethylamine (60 .mu.L), and
dichloromethane (3.2 mL) was ice-cooled, and cyclopropanecarboxylic
acid chloride (21 .mu.L) was added thereto, followed by stirring at
the same temperature for 15 minutes and at room temperature for 45
minutes. Then, ethyl acetate (15 mL) and water (15 mL) were added
to the reaction mixture to carry out liquid separation, and the
organic layer was washed with 0.1 M hydrochloric acid (15 mL), a
saturated aqueous sodium hydrogen carbonate solution (15 mL), and
saturated brine (15 mL) in this order, dried over anhydrous
magnesium sulfate, and then filtered, and the filtrate was
concentrated under reduced pressure. To the residue were added
dioxane (2 mL) and pyridinium p-toluenesulfonite (2.4 mg), followed
by heating and stirring at 100.degree. C. for 48 hours, and toluene
(4 mL) was added thereto, followed by heating and stirring for an
additional 24 hours. The reaction mixture was cooled to room
temperature, and ethyl acetate (15 mL) and water (15 mL) were added
thereto to carry out liquid separation. The organic layer was
washed with 0.1 M hydrochloric acid (15 mL), a saturated aqueous
sodium hydrogen carbonate solution (15 mL), and saturated brine (15
mL) in this order, dried over anhydrous magnesium sulfate, and then
filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by thin film silica gel chromatography to
obtain
3-{[6-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-5-isopropoxy--
N-(1-methyl-1H-pyrazol-3-yl)benzamide (34 mg) as a colorless
oil.
Example 15
[0277] To a solution of
3-isopropoxy-N-(1-methyl-1H-pyrazol-3-yl)-5-({6-[5-(methylsulfanyl)-1,2,4-
-oxadiazol-3-yl]pyridin-3-yl}oxy)benzamide (115 mg) in NMP (1 mL)
was added a 2 M methylamine/THF solution (1 mL), followed by
stirring at room temperature for 24 hours. To the reaction mixture
were added diethyl ether (10 mL), ethyl acetate (10 mL), and water
(15 mL) to carry out liquid separation. The organic layer was
washed with water (15 mL) and saturated brine (15 mL) in this
order, dried over anhydrous magnesium sulfate, and then filtered,
and the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane-ethyl acetate=1:1 to 1:2 to 1:3 to 0:1), and the residue
was washed with diisopropyl ether to obtain
3-({6-[5-(dimethylamino)-1,2,4-oxadiazol-3-yl]pyridin-3-yl}oxy)-5-isoprop-
oxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (80 mg) as a pale yellow
amorphous substance.
Example 16
[0278] 5-[5-(3-{[1-({[tert-Butyl
(dimethyl)silyl]oxy}methyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)c-
arbamoyl]phenoxy)pyrazin-2-yl]-N-methyl-1,2,4-oxadiazole-3-carboxamide
(159 mg), and THF (5 mL) were mixed, and 1 M hydrochloric acid
(1.26 mL) was added thereto, followed by stirring for 30 minutes.
Further, 1 M hydrochloric acid (1.26 mL) was added thereto,
followed by stirring at an oil bath temperature of 55.degree. C.
for 1 hour. The reaction mixture was diluted with ethyl acetate,
washed with water, a saturated aqueous sodium hydrogen carbonate
solution, and a saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography (hexane:ethyl acetate=7:3 to 0:1). The obtained
residue was washed with ethyl acetate and collected by filtration
to obtain
5-[5-(3-{[1-(hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)c-
arbamoyl]phenoxy)pyrazin-2-yl]-N-methyl-1,2,4-oxadiazole-3-carboxamide
(47 mg) as a white solid.
Example 17
[0279]
5-(3-{[1-(Hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-y-
l)carbamoyl]phenoxy)pyridine-2-carboxylic acid (264 mg) and NMP
(5.3 mL) were mixed, and EDCI (174 mg),
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAT) (123 mg), ethyl
2-oxyiminooxamate (120 mg), and triethylamine (0.255 mL) were added
thereto, followed by stirring at room temperature for 1 hour,
stirring at an oil bath temperature of 80.degree. C. for 2 hours
and then stirring at 100.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
washed with water, a 1 M aqueous sodium hydroxide solution, and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=7:3 to 2:8).
[0280] The obtained residue and THF (6 mL) were mixed, and a 2 M
methylamine/THF solution (1.51 mL) was added thereto, followed by
stirring for 1 hour. Further, ethanol (1 mL) and a 2 M
methylamine/THF solution (1.51 mL) were added thereto, followed by
stirring for 30 minutes. The reaction mixture was concentrated
under reduced pressure, diluted with ethyl acetate, washed with
water, a saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:methanol=1:0 to 19:1). The
obtained residue was washed with hexane and collected by filtration
to obtain
5-[5-(3-{[1-(hydroxymethyl)cyclobutyl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)c-
arbamoyl]phenoxy)pyridin-2-yl]-N-methyl-1,2,4-oxadiazole-3-carboxamide
(62 mg) as a white amorphous substance.
Example 18
[0281]
3-{[5-(Hydrazinocarbonyl)pyrazin-2-yl]oxy}-5-isopropoxy-N-(1-methyl-
-1H-pyrazol-3-yl)benzamide (393 mg), THF (10 mL), and triethylamine
(0.4 mL) were mixed, and ethylchloro(oxo)acetate (0.16 mL) was
added thereto under ice-cooling, followed by stirring for 15
minutes. NMP (2 mL) was added thereto, followed by stirring at room
temperature for 1 hour. The reaction mixture was diluted with ethyl
acetate, and washed with water, and a saturated aqueous sodium
chloride solution. The organic layer was concentrated under reduced
pressure.
[0282] The obtained residue, dichloromethane (8 mL), and pyridine
(0.310 mL) were mixed, and under ice-cooling,
trifluoromethanesulfonic anhydride (0.320 mL) was added thereto,
followed by stirring for 30 minutes. The reaction mixture was
diluted with ethyl acetate, washed with water, a saturated aqueous
sodium hydrogen carbonate solution, a saturated aqueous ammonium
chloride solution, and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=7:3 to 3:7).
[0283] The obtained residue and ethanol (5 mL) were mixed, and a 2
M methylamine/THF solution (0.480 mL) was added thereto under
ice-cooling, followed by stirring for 30 minutes. The reaction
mixture was diluted with ethyl acetate, washed with water, and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1 to 0:1). The
obtained solid was washed with hexane and collected by filtration
to obtain
5-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazin-
-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide (20 mg) as a white
amorphous substance.
Example 19
[0284] To a solution of
3-hydroxy-5-{[(2S)-1-methoxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-
benzamide (400 mg) in NMP (10 mL) were added potassium carbonate
(362 mg) and
5-(5-fluoropyridin-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide
(320 mg) at room temperature under a nitrogen air flow, followed by
stirring at an oil bath temperature of 110.degree. C. for 3 hours.
5-(5-Fluoropyridin-2-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide
(29 mg) was added thereto, followed by stirring at 110.degree. C.
for 1 hour. After leaving to stand for cooling to room temperature,
water was added thereto, followed by extraction with ethyl acetate.
The organic layer was washed with water and saturated brine, and
dried over anhydrous magnesium sulfate, and then the drying agent
was removed. The solvent was evaporated under reduced pressure and
the obtained crude product was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1 to 1:10) to obtain
5-[5-(3-{[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy)pyridin-2-yl]-N-methyl-1,3,4-oxadiazole-2-carboxamide
(632 mg) as a white amorphous substance.
Example 20
[0285] To a solution of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoic
acid (80 mg) in DMF (3 mL) were added 1,3-thiazole-2-amine (45 mg),
EDCI (50 mg), and HOBt (30 mg), followed by stirring at room
temperature for 4 hours. Water (20 mL) and ethyl acetate (20 mL)
were added thereto, and the organic layer was washed with 1 M
hydrochloric acid (20 mL), a saturated aqueous sodium hydrogen
carbonate solution (20 mL), and saturated brine (20 mL), and dried
over anhydrous magnesium sulfate. Then, the solvent was evaporated
under reduced pressure to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxy-N-1,3-thiazol--
2-ylbenzamide (85 mg) as a colorless amorphous substance.
Example 21
[0286] A mixture of
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-isopropoxy-N-1,3-thiazol-2-ylbe-
nzamide (75 mg), propanoyl chloride (0.027 mL), and pyridine (1 mL)
was stirred at room temperature for 2 hours. To the reaction
mixture was added water, followed by extraction with ethyl acetate.
The organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate, and the solvent was evaporated. The
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=50:50) to obtain
3-{4-[(cyclopropylmethyl)(propionyl)amino]phenoxy}-5-isopropoxy-N-1,3-thi-
azol-2-ylbenzamide (70 mg) as a white amorphous substance.
Example 22
[0287] A mixture of
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropoxy-N-(1-methy-
l-1H-pyrazol-3-yl)benzamide (75 mg), isoxazole-5-carboxylic acid
chloride (233 mg), 4-dimethylaminopyridine (217 mg), and
dichloromethane (0.5 mL) was stirred at room temperature for 1
hour. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate:hexane=70:30) to obtain
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)-1,2-oxazole-5-carboxamide (70 mg) as a
white amorphous substance.
Example 23
[0288] A mixture of tetrahydro-2H-pyran-4-carboxylic acid (738 mg),
oxalyl chloride (0.49 mL), DMF (0.044 mL), and dichloromethane (5
mL) was stirred at room temperature for 30 minutes. To the reaction
mixture were added
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-isopropoxy-N-(1-
-methyl-1H-pyrazol-3-yl)benzamide (798 mg), and
4-dimethylaminopyridine (400 mg), followed by stirring at room
temperature overnight. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=70:30) to obtain
N-(cyclopropylmethyl)-N-(5-{3-isopropoxy-5-[(1-methyl-1H-pyrazol-3-yl)car-
bamoyl]phenoxy}pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxamide (800
mg) as a light yellow amorphous substance.
Example 24
[0289] A mixture of tetrahydro-2H-pyran-4-carboxylic acid (591 mg),
oxalyl chloride (0.39 mL), DMF (0.035 mL), and dichloromethane (5
mL) was stirred at room temperature for 20 minutes. To the reaction
mixture were added
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-N-(1-methyl-1H-py-
razol-3-yl)-5-({(2S)-1-[(triisopropylsilyl)oxy]propan-2-yl}oxy)benzamide
(270 mg) and 4-dimethylaminopyridine (555 mg), followed by stirring
at room temperature for 1 hour. To the reaction mixture was added
water, followed by extraction with ethyl acetate. The organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=50:50) to obtain a light yellow oil. A mixture of
this oil and N,N,N-tributylbutane-1-ammonium fluoride (1 M solution
in THF, 2 mL) was stirred at room temperature for 10 minutes, and
the solvent was evaporated. The obtained residue was purified by
silica gel column chromatography (methanol:chloroform=3:97) to
obtain
N-(cyclopropylmethyl)-N-[5-(3-{[(2S)-1-hydroxypropan-2-yl]oxy}--
5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy)pyrazin-2-yl]tetrahydro-2H--
pyran-4-carboxamide (86 mg) as a white amorphous substance.
Example 25
[0290] To a solution of tert-butyl
3-[(3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-met-
hylethoxy]benzoyl)amino]-1H-pyrazole-1-carboxylate (181 mg) in
dichloromethane (10 mL) was added trifluoroacetic acid (0.48 mL) at
room temperature, followed by stirring at room temperature
overnight, concentrating under reduced pressure, and carrying out
liquid separation with ethyl acetate and a saturated aqueous sodium
hydrogen carbonate solution. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated. The obtained crude product was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1,
chloroform:methanol=1:0 to 10:1) to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-methyle-
thoxy]-N-1H-pyrazol-3-ylbenzamide (133 mg) as a white amorphous
substance.
Example 26
[0291] To a solution of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-({1-[(benzyloxy)methyl]cy-
clobutyl}methoxy)-N-1,3-thiazol-2-ylbenzamide (176 mg) in
trifluoroacetic acid (5 mL) was added 1,2,3,4,5-pentamethylbenzene
(427 mg) at room temperature, followed by stirring at room
temperature overnight. After concentration, a saturated aqueous
sodium hydrogen carbonate solution was added thereto, followed by
extraction with ethyl acetate, and the organic layer was washed
with saturated brine. The organic layer was dried over anhydrous
magnesium sulfate and concentrated. The obtained crude product was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1 to 1:2) to obtain an oily substance. To a solution of
this oily substance in methanol (5 mL) was added a 1 M aqueous
sodium hydroxide solution (1 mL) at room temperature, followed by
stirring at room temperature for 2 hours, and 1 M hydrochloric acid
was added thereto at room temperature, followed by extraction with
ethyl acetate. The organic layer was washed with saturated brine.
The organic layer was dried over anhydrous magnesium sulfate and
concentrated to obtain a colorless oily substance. A solvent
(diisopropyl etherhexane=1:1) was added thereto and the precipitate
was collected by filtration to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-{[1-(hydroxymethyl)cyclob-
utyl]methoxy}-N-1,3-thiazol-2-ylbenzamide (101 mg) as a white
solid.
Example 27
[0292] To a solution of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoic
acid (220 mg) and methyl 6-aminonicotinate (105 mg) in pyridine
(4.4 mL) was added phosphorous oxychloride (0.06 mL) at -5.degree.
C., followed by stirring at the same temperature for 0.5 hours. The
reaction mixture was stirred at room temperature overnight, and
then diluted with ethyl acetate. The organic layer was washed with
a 10% aqueous citric acid solution and saturated brine, and dried
over anhydrous magnesium sulfate. After concentration, to the
residue was added methanol (0.6 mL), followed by stirring for 0.5
hours. After concentration, the residue was purified by silica gel
column chromatography (0 to 5% methanol/chloroform) to obtain
methyl
6-[(3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoyl)ami-
no]nicotinate (203 mg) as a colorless amorphous substance.
Example 28
[0293] To a solution of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-methoxy-1-methyle-
thoxy]-N-1H-pyrazol-3-ylbenzamide (100 mg) in acetonitrile (5 mL)
was added iodo(trimethyl)silane (0.15 mL) under ice-cooling,
followed by stirring at room temperature overnight. Then,
iodo(trimethyl)silane (0.2 mL) was added thereto at room
temperature, followed by stirring at room temperature for 3 hours,
and then a saturated aqueous sodium hydrogen carbonate solution was
added thereto under ice-cooling, followed by extraction with ethyl
acetate. The organic layer was washed with a saturated aqueous
sodium thiosulfate solution and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated. To a solution of the
obtained oily substance in methanol solution (4 mL) was added a 1 M
aqueous sodium hydroxide solution (1 mL) at room temperature,
followed by stirring at room temperature for 1 hour and
neutralizing by the addition of 1 M hydrochloric acid at room
temperature. Then, saturated brine was added thereto, followed by
extraction with a solvent (chloroform:isopropyl alcohol=4:1). The
organic layer was dried over anhydrous magnesium sulfate and
concentrated. The obtained crude product was purified by silica gel
column chromatography (hexane:ethyl acetate=1:1,
chloroform:methanol=1:0 to 10:1). The obtained white amorphous
substance was purified by thin film chromatography
(chloroform:methanol=10:1) to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1S)-2-hydroxy-1-methyle-
thoxy]-N-1H-pyrazol-3-ylbenzamide (56 mg) as a white amorphous
substance.
Example 29
[0294] A mixture of
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-5-{[(2S)-1-methoxypropa-
n-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (136 mg),
chloroacetyl chloride (0.024 mL), 4-dimethylaminopyridine (37 mg),
and dichloromethane (2 mL) was stirred at room temperature for 2
hours. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated.
[0295] The obtained residue was purified by silica gel column
chromatography (ethyl acetate:hexane=70:30) to obtain a white
amorphous substance. N,N-Dimethylamine (2 M solution in THF, 2 mL)
was added thereto, followed by stirring at room temperature for 2
hours, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography
(methanol:chloroform=4:96) to obtain
3-({5-[cyclopropylmethyl)(N,N-dimethylglycyl)amino]pyrazin-2-yl}oxy)-5-{[-
(2S)-1-methoxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide
(135 mg) as a white amorphous substance.
Example 30
[0296] A mixture of
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-N-[4-(2,2-dimethyl-1,3-diox-
olan-4-yl)-1,3-thiazol-2-yl]-5-isopropoxybenzamide (95 mg), THF (1
mL), and 1 M hydrochloric acid (1 mL) was stirred at 50.degree. C.
for 1 hour. The reaction mixture was concentrated, then dissolved
in chloroform, and washed with saturated brine. The organic layer
was dried over anhydrous magnesium sulfate and then concentrated to
obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-N-[4-(1,2-dihydroxyethyl)-1-
,3-thiazol-2-yl]-5-isopropoxybenzamide (75 mg) as a colorless
amorphous substance.
Example 31
[0297] A mixture of
2-[(cyclopropylmethyl){4-[3-isopropoxy-5-(1,3-thiazol-2-ylcarbamoyl)pheno-
xy]phenyl}amino]-2-oxoethylacetate (50 mg), potassium carbonate (13
mg), and methanol (2 mL) was stirred at room temperature for 2
hours. To the reaction mixture was added water, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate) to obtain
3-{4-[(cyclopropylmethyl)(glycoloyl)amino]phenoxy}-5-isopropoxy-
-N-1,3-thiazol-2-ylbenzamide (40 mg) as a white amorphous
substance.
Example 32
[0298] A mixture of
3-{4-[(cyclopropylmethyl)amino]phenoxy}-5-isopropoxy-N-1,3-thiazol-2-ylbe-
nzamide (80 mg), dimethylcarbamoyl chloride (0.076 mL), and
pyridine (1 mL) was stirred at 80.degree. C. for 3 hours. To the
reaction mixture was added 1 M hydrochloric acid, followed by
extraction with ethyl acetate. The organic layer was washed with
saturated brine and dried over anhydrous sodium sulfate, and the
solvent was evaporated. The obtained residue was purified by silica
gel column chromatography (ethyl acetate) to obtain a white
amorphous substance. A mixture of the obtained amorphous substance,
a 1 M aqueous sodium hydroxide solution (1 mL), and methanol (1 mL)
was stirred at room temperature for 3 hours. To the reaction
mixture was added 1 M hydrochloric acid, followed by extraction
with ethyl acetate. The organic layer was washed with saturated
brine and dried over anhydrous sodium sulfate, and the solvent was
evaporated. The obtained residue was purified by silica gel column
chromatography (ethyl acetate) to obtain
3-{4-[(cyclopropylmethyl)(dimethylcarbamoyl)amino]phenoxy}-5-isopropoxy-N-
-1,3-thiazol-2-ylbenzamide (30 mg) as a white amorphous
substance.
Example 33
[0299] To a solution of
6-[(3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoyl)ami-
no]nicotinic acid (200 mg) in THF (5 mL) was added
N,N'-carbonyldiimidazole (100 mg), followed by stirring at room
temperature for 1 hour, and then sodium borohydride (22 mg) was
dissolved in about 0.2 mL of water, which was then added to the
reaction mixture at -5.degree. C. or lower. After stirring at
5.degree. C. or lower for 0.5 hours, water and saturated brine were
added to the reaction mixture, followed by extraction with ethyl
acetate. The organic layer was washed with saturated brine, and
then the organic layer was dried over anhydrous magnesium sulfate.
After concentration, the residue was purified by silica gel column
chromatography (0 to 5% methanol/chloroform) to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-N-[5-(hydroxymethyl)pyridin-
-2-yl]-5-isopropoxybenzamide (120 mg).
Example 34
[0300] To a solution of methyl
6-[(3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoyl)ami-
no]nicotinate (520 mg) in dioxane (5 mL) was added a 1 M aqueous
sodium hydroxide solution (1.2 mL), followed by stirring overnight.
The reaction mixture was neutralized with 1 M hydrochloric acid and
extracted with chloroform. The organic layer was dried over
anhydrous magnesium sulfate and then concentrated, and the residue
was purified by silica gel column chromatography (0 to 10%
methanol/chloroform) to obtain
6-[(3-{44acetyl(cyclopropylmethyl)amino]phenoxy}-5-isopropoxybenzoyl)amin-
o]nicotinic acid (430 mg).
Example 35
[0301]
(3-{4-[Acetyl(cyclopropylmethyl)amino]phenoxy}-5-[(1-methyl-1H-pyra-
zol-3-yl)carbamoyl]phenoxy)acetic acid (70 mg), DMF (3 mL), and
N,N'-carbonyldiimidazole (48 mg) were mixed, followed by stirring
at an oil bath temperature of 50.degree. C. for 1 hour.
[0302] Methanesulfonamide (56 mg) and DBU (0.088 mL) were added,
followed by stirring for 2 hours. The reaction mixture was cooled
to room temperature, and water and 1 M hydrochloric acid were added
thereto, followed by extraction with ethyl acetate. The organic
layer was washed with water and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography
(chloroform:methanol=10:0 to 9:1). The obtained oily substance was
dissolved in ethyl acetate and added dropwise to hexane. The
solvent was evaporated under reduced pressure. The obtained solid
was washed with diisopropyl ether and collected by filtration to
obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-N-(1-methyl-1H-pyrazol-3-yl-
)-5-{2-[(methylsulfonyl)amino]-2-oxo ethoxy}benzamide (40 mg) as a
white solid.
Example 36
[0303] Methyl
3-{4-[Acetyl(cyclopropylmethyl)amino]phenoxy}-5-hydroxybenzoate
(300 mg), potassium carbonate (467 mg),
2-chloro-N,N-dimethylethanamine hydrochloride (244 mg), and DMF (3
mL) were mixed, followed by stirring at an oil bath temperature of
60.degree. C. for 2 hours. The reaction mixture was cooled to room
temperature, and water was added thereto, followed by extraction
with ethyl acetate. The organic layer was washed with water and a
saturated aqueous sodium chloride solution, and dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The obtained residue was purified by silica gel
column chromatography (chloroform:methanol=100:0 to 95:5).
[0304] The obtained residue and methanol (6 mL) were mixed, and a 1
M aqueous sodium hydroxide solution (1.01 mL) was added thereto,
followed by stirring at room temperature for 1 hour. Further, a 1 M
aqueous sodium hydroxide solution (1.01 mL) was added thereto,
followed by stirring at an oil bath temperature of 60.degree. C.
for 1 hour. The reaction mixture was returned to room temperature
and concentrated under reduced pressure. Water and 1 M hydrochloric
acid (2.02 mL) were added thereto, followed by extraction with a
mixed solution of chloroform/isopropanol (4:1). The organic layer
was washed with water and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure.
[0305] The obtained residue, 1-methyl-1H-pyrazole-3-amine (164 mg),
EDCI (243 mg), HOBt (171 mg), and DMF (6 mL) were mixed, followed
by stirring at an oil bath temperature of 60.degree. C. for 30
minutes. To the reaction mixture were added water and a 1 M aqueous
sodium hydroxide solution, followed by extraction with ethyl
acetate. The organic layer was washed with water, a 1 M aqueous
sodium hydroxide solution, and a saturated aqueous sodium chloride
solution, and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The obtained residue
was purified by silica gel column chromatography
(chloroform:methanol=10:0 to 95:5). The obtained oily substance was
dissolved in ethyl acetate, and added dropwise to hexane. The
solvent was evaporated under reduced pressure to obtain
3-{4-[acetyl(cyclopropylmethyl)amino]phenoxy}-5-[2-(dimethylamino)ethoxy]-
-N-(1-methyl-1H-pyrazol-3-yl)benzamide (64 mg) as a white amorphous
substance.
Example 37
[0306] To a solution of
3-{4-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]phenoxy}-
-5-{[(2S)-1-methoxypropan-2-yl]oxy}benzoic acid (497 mg) in
dichloromethane (10 mL) were added 1 M oxalyl
chloride/dichloromethane (1.13 mL) and DMF (3 droplets) under
ice-cooling, followed by stirring at room temperature for 30
minutes. 1-Methyl-1H-pyrazole-3-amine (120 mg) and pyridine (0.17
mL) were added thereto under ice-cooling, followed by stirring at
room temperature for 2 hours. Water was added thereto, followed by
extraction with ethyl acetate, and the organic layer was washed
with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen
carbonate solution, and saturated brine, and dried over anhydrous
magnesium sulfate. Then, the solvent was evaporated under reduced
pressure, and the obtained crude product was purified by silica gel
column chromatography (hexane:ethyl acetate=2:1 to 1:10) to obtain
N-(cyclopropylmethyl)-N-[4-(3-[(2S)-1-methoxypropan-2-yl]oxy}-5-[(1-methy-
l-1H-pyrazol-3-yl)carbamoyl]phenoxy)phenyl]tetrahydro-2H-pyran-4-carboxami-
de (334 mg) as a white amorphous substance.
Example 38
[0307] To a solution of
N-(5-{3-(benzyloxy)-5-[(1-methyl-1H-pyrazol-3-yl)carbamoyl]phenoxy}pyrazi-
n-2-yl)-N-(cyclopropylmethyl)tetrahydro-2H-pyran-4-carboxamide (107
mg) in ethyl acetate (10 mL) was added 10% palladium/carbon (30
mg), followed by stirring for 8 hours under a hydrogen atmosphere
of 0.3 MPa. The reaction mixture was filtered using Celite and the
filtrate was concentrated. To a solution of the obtained oily
substance in ethyl acetate (10 mL) was added 10% palladium/carbon
(50 mg), followed by stirring for 8 hours under a hydrogen
atmosphere of 0.3 MPa. Further, the reaction mixture was filtered
using Celite and the filtrate was concentrated. To a solution of
the obtained oily substance in ethyl acetate (10 mL) was added 10%
palladium/carbon (50 mg), followed by stirring for 21 hours under a
hydrogen atmosphere of 0.3 MPa. Then the reaction mixture was
filtrated using Celite and the filtrate was concentrated to obtain
N-(cyclopropylmethyl)-N-(5-{3-hydroxy-5-[(1-methyl-1H-pyrazol-3-yl)carbam-
oyl]phenoxy}pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxamide (70 mg)
as a white amorphous substance.
Example 39
[0308] A mixture of methyl
3-({5-[(cyclopropylmethyl)(tetrahydro-2H-pyran-4-ylcarbonyl)amino]pyrazin-
-2-yl}oxy)-5-isopropoxybenzoate (162 mg), a 1 M aqueous sodium
hydroxide solution (2 mL), ethanol (2 mL), and THF (2 mL) was
stirred at room temperature for 20 minutes. To the reaction mixture
was added hydrochloric acid, followed by extraction with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous sodium sulfate, and the solvent was evaporated
to obtain a white amorphous substance. A mixture of this amorphous
substance, tert-butyl 3-amino-1H-pyrazole-1-carboxylate (121 mg),
N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N--
methylmethaneaminiumhexafluorophosphate (167 mg),
4-dimethylaminopyridine (54 mg), and DMF (0.4 mL) was stirred at
50.degree. C. overnight. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=50:50) to obtain a colorless oily substance.
[0309] To the obtained oily substance were added trifluoroacetic
acid (2 mL) and chloroform (2 mL), followed by stirring at room
temperature for 2 hours. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=85:15) to obtain
N-(cyclopropylmethyl)-N-{5-[3-isopropoxy-5-(1H-pyrazol-3-ylcarbamo-
yl)phenoxy]pyrazin-2-yl}tetrahydro-2H-pyran-4-carboxamide (77 mg)
as a light yellow amorphous substance.
Example 40
[0310] A mixture of
3-({5-[(cyclopropylmethyl)amino]pyrazin-2-yl}oxy)-N-(1-methyl-1H-pyrazol--
3-yl)-5-({(2S)-1-[(triisopropylsilyl)oxy]propan-2-yl}oxy)benzamide
(200 mg), chloroacetyl chloride (0.27 mL), 4-dimethylaminopyridine
(411 mg), and dichloromethane (1.3 mL) was stirred at room
temperature for 1 hour. To the reaction mixture was added water,
followed by extraction with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate, and the solvent was evaporated. The obtained residue was
purified by silica gel column chromatography (ethyl acetate) to
obtain a white amorphous substance.
[0311] To the obtained amorphous substance was added
N,N-dimethylamine (2 M solution in THF, 3 mL), followed by stirring
at room temperature for 2 hours. The solvent was evaporated, and to
the obtained residue was added N,N,N-tributylbutane-1-ammonium
fluoride (1 M solution in THF, 2 mL), followed by stirring at room
temperature for 5 minutes. The solvent was evaporated and the
obtained residue was purified by silica gel column chromatography
(methanol/chloroform=8/92) to obtain a light yellow oily substance.
To this oily substance was added water, followed by extraction with
chloroform. The organic layer was extracted with hydrochloric acid,
and the aqueous layer was neutralized with an aqueous sodium
hydroxide solution and extracted from chloroform. The organic layer
was dried over anhydrous sodium sulfate and the solvent was
evaporated. The obtained residue was purified by silica gel column
chromatography (methanol/chloroform=8/92) to obtain
3-({5-[(cyclopropylmethyl)(N,N-dimethylglycyl)amino]pyrazin-2-yl}oxy)-5-[-
(2S)-1-hydroxypropan-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide
as a white amorphous substance (69 mg).
[0312] The Example Compounds 41 to 177 were prepared in the same
manner as the methods of Examples 1 to 40. For the Example
Compounds, the structures are shown in Tables 51 to 95 below, and
the preparation methods and the physicochemical data are shown in
Tables 102 to 110.
[0313] Furthermore, the following abbreviations are used in Tables
to be described later. PEx: Preparation Example number, Ex: Example
number, Data: Physicochemical data (EI: m/z value in EI-MS, FAB+:
m/z value in FAB-MS (positive ion), FAB-: m/z value in FAB-MS
(negative ion), ESI+: m/z value in ESI-MS (positive ion), ESI-: m/z
value in ESI-MS (negative ion), CI+: m/z value in CI-MS (positive
ion), m/z value in CI-MS (positive ion), APCI+: m/z value in
APCI-MS (positive ion), APCl/ESI+: simultaneous measurement of
APCI+ and ESI+, NMR1: .delta.(ppm) in 1H NMR in DMSO-d.sub.6, NMR2:
.delta.(ppm) in 1H NMR in CDCl.sub.3, Structure: Structural formula
(HCl in the structural formula represents hydrochloride), Syn:
Production method (the numeral shows that in the same manner as in
the Example compound having the number as its Example number, the
compound was prepared using the corresponding starting material),
PSyn: Production method (the numeral shows that in the same manner
as in the Preparation Example compound having the number as its
Preparation Example number, the compound was prepared using the
corresponding starting material), tBu: tert-butyl, Boc:
tert-butoxycarbonyl.
[0314] Moreover,
##STR00003##
[0315] means that the double bond is a mixture of E forms and Z
forms.
TABLE-US-00004 TABLE 4 PEx Structure 1 ##STR00004## 2 ##STR00005##
3 ##STR00006## 4 ##STR00007## 5 ##STR00008##
TABLE-US-00005 TABLE 5 PEx Structure 6 ##STR00009## 7 ##STR00010##
8 ##STR00011## 9 ##STR00012##
TABLE-US-00006 TABLE 6 PEx Structure 10 ##STR00013## 11
##STR00014## 12 ##STR00015## 13 ##STR00016## 14 ##STR00017##
TABLE-US-00007 TABLE 7 PEx Structure 15 ##STR00018## 16
##STR00019## 17 ##STR00020## 18 ##STR00021## 19 ##STR00022##
TABLE-US-00008 TABLE 8 PEx Structure 20 ##STR00023## 21
##STR00024## 22 ##STR00025## 23 ##STR00026##
TABLE-US-00009 TABLE 9 PEx Structure 24 ##STR00027## 25
##STR00028## 26 ##STR00029## 27 ##STR00030##
TABLE-US-00010 TABLE 10 PEx Structure 28 ##STR00031## 29
##STR00032## 30 ##STR00033## 31 ##STR00034## 32 ##STR00035## 33
##STR00036##
TABLE-US-00011 TABLE 11 PEx Structure 34 ##STR00037## 35
##STR00038## 36 ##STR00039## 37 ##STR00040## 38 ##STR00041##
TABLE-US-00012 TABLE 12 PEx Structure 39 ##STR00042## 40
##STR00043## 41 ##STR00044## 42 ##STR00045##
TABLE-US-00013 TABLE 13 PEx Structure 43 ##STR00046## 44
##STR00047## 45 ##STR00048## 46 ##STR00049##
TABLE-US-00014 TABLE 14 PEx Structure 47 ##STR00050## 48
##STR00051## 49 ##STR00052## 50 ##STR00053##
TABLE-US-00015 TABLE 15 PEx Structure 51 ##STR00054## 52
##STR00055## 53 ##STR00056## 54 ##STR00057##
TABLE-US-00016 TABLE 16 PEx Structure 55 ##STR00058## 56
##STR00059## 57 ##STR00060## 58 ##STR00061##
TABLE-US-00017 TABLE 17 PEx Structure 59 ##STR00062## 60
##STR00063## 61 ##STR00064## 62 ##STR00065## 63 ##STR00066##
TABLE-US-00018 TABLE 18 PEx Structure 64 ##STR00067## 65
##STR00068## 66 ##STR00069##
TABLE-US-00019 TABLE 19 PEx Structure 67 ##STR00070## 68
##STR00071## 69 ##STR00072## 70 ##STR00073##
TABLE-US-00020 TABLE 20 PEx Structure 71 ##STR00074## 72
##STR00075## 73 ##STR00076## 74 ##STR00077##
TABLE-US-00021 TABLE 21 PEx Structure 75 ##STR00078## 76
##STR00079## 77 ##STR00080##
TABLE-US-00022 TABLE 22 PEx Structure 78 ##STR00081## 79
##STR00082## 80 ##STR00083## 81 ##STR00084##
TABLE-US-00023 TABLE 23 PEx Structure 82 ##STR00085## 83
##STR00086## 84 ##STR00087## 85 ##STR00088##
TABLE-US-00024 TABLE 24 PEx Structure 86 ##STR00089## 87
##STR00090## 88 ##STR00091## 89 ##STR00092##
TABLE-US-00025 TABLE 25 PEx Structure 90 ##STR00093## 91
##STR00094## 92 ##STR00095## 93 ##STR00096##
TABLE-US-00026 TABLE 26 PEx Structure 94 ##STR00097## 95
##STR00098## 96 ##STR00099## 97 ##STR00100##
TABLE-US-00027 TABLE 27 PEx Structure 98 ##STR00101## 99
##STR00102## 100 ##STR00103## 101 ##STR00104##
TABLE-US-00028 TABLE 28 PEx Structure 102 ##STR00105## 103
##STR00106## 104 ##STR00107## 105 ##STR00108##
TABLE-US-00029 TABLE 29 PEx Structure 106 ##STR00109## 107
##STR00110## 108 ##STR00111## 109 ##STR00112##
TABLE-US-00030 TABLE .30 PEx Structure 110 ##STR00113## 111
##STR00114## 112 ##STR00115## 113 ##STR00116##
TABLE-US-00031 TABLE 31 PEx Structure 114 ##STR00117## 115
##STR00118## 116 ##STR00119## 117 ##STR00120## 118 ##STR00121##
TABLE-US-00032 TABLE 32 PEx Structure 119 ##STR00122## 120
##STR00123## 121 ##STR00124## 122 ##STR00125##
TABLE-US-00033 TABLE 33 PEx Structure 123 ##STR00126## 124
##STR00127## 125 ##STR00128##
TABLE-US-00034 TABLE 34 PEx Structure 126 ##STR00129## 127
##STR00130## 128 ##STR00131## 129 ##STR00132##
TABLE-US-00035 TABLE 35 PEx Structure 130 ##STR00133## 131
##STR00134## 132 ##STR00135## 133 ##STR00136## 134 ##STR00137##
TABLE-US-00036 TABLE 36 PEx Structure 135 ##STR00138## 136
##STR00139## 137 ##STR00140## 138 ##STR00141##
TABLE-US-00037 TABLE 37 PEx Structure 139 ##STR00142## 140
##STR00143## 141 ##STR00144## 142 ##STR00145##
TABLE-US-00038 TABLE 38 PEx Structure 143 ##STR00146## 144
##STR00147## 145 ##STR00148## 146 ##STR00149##
TABLE-US-00039 TABLE 39 PEx Structure 147 ##STR00150## 148
##STR00151## 149 ##STR00152## 150 ##STR00153##
TABLE-US-00040 TABLE 40 PEx Structure 151 ##STR00154## 152
##STR00155## 153 ##STR00156## 154 ##STR00157##
TABLE-US-00041 TABLE 41 PEx Structure 155 ##STR00158## 156
##STR00159## 157 ##STR00160## 158 ##STR00161##
TABLE-US-00042 TABLE 42 PEx Structure 159 ##STR00162## 160
##STR00163## 161 ##STR00164## 162 ##STR00165##
TABLE-US-00043 TABLE 43 PEx Structure 163 ##STR00166## 164
##STR00167## 165 ##STR00168## 166 ##STR00169##
TABLE-US-00044 TABLE 44 PEx Structure 167 ##STR00170## 168
##STR00171## 169 ##STR00172## 170 ##STR00173##
TABLE-US-00045 TABLE 45 PEx Structure 171 ##STR00174## 172
##STR00175## 173 ##STR00176## 174 ##STR00177##
TABLE-US-00046 TABLE 46 PEx Structure 175 ##STR00178## 176
##STR00179## 177 ##STR00180## 178 ##STR00181##
TABLE-US-00047 TABLE 47 PEx Structure 179 ##STR00182## 180
##STR00183## 181 ##STR00184## 182 ##STR00185##
TABLE-US-00048 TABLE 48 PEx Structure 183 ##STR00186## 184
##STR00187## 185 ##STR00188## 186 ##STR00189##
TABLE-US-00049 TABLE 49 PEx Structure 187 ##STR00190## 188
##STR00191## 189 ##STR00192## 190 ##STR00193##
TABLE-US-00050 TABLE 50 PEx Structure 191 ##STR00194## 192
##STR00195## 193 ##STR00196##
TABLE-US-00051 TABLE 51 Ex Structure 1 ##STR00197## 2 ##STR00198##
3 ##STR00199## 4 ##STR00200##
TABLE-US-00052 TABLE 52 Ex Structure 5 ##STR00201## 6 ##STR00202##
7 ##STR00203## 8 ##STR00204##
TABLE-US-00053 TABLE 53 Ex Structure 9 ##STR00205## 10 ##STR00206##
11 ##STR00207## 12 ##STR00208##
TABLE-US-00054 TABLE 54 Ex Structure 13 ##STR00209## 14
##STR00210## 15 ##STR00211## 16 ##STR00212##
TABLE-US-00055 TABLE 55 Ex Structure 17 ##STR00213## 18
##STR00214## 19 ##STR00215## 20 ##STR00216##
TABLE-US-00056 TABLE 56 Ex Structure 21 ##STR00217## 22
##STR00218## 23 ##STR00219##
TABLE-US-00057 TABLE 57 Ex Structure 24 ##STR00220## 25
##STR00221## 26 ##STR00222## 27 ##STR00223##
TABLE-US-00058 TABLE 58 Ex Structure 28 ##STR00224## 29
##STR00225## 30 ##STR00226## 31 ##STR00227##
TABLE-US-00059 TABLE 59 Ex Structure 32 ##STR00228## 33
##STR00229## 34 ##STR00230## 35 ##STR00231##
TABLE-US-00060 TABLE 60 Ex Structure 36 ##STR00232## 37
##STR00233## 38 ##STR00234## 39 ##STR00235##
TABLE-US-00061 TABLE 61 Ex Structure 40 ##STR00236## 41
##STR00237## 42 ##STR00238## 43 ##STR00239##
TABLE-US-00062 TABLE 62 Ex Structure 44 ##STR00240## 45
##STR00241## 46 ##STR00242## 47 ##STR00243##
TABLE-US-00063 TABLE 63 Ex Structure 48 ##STR00244## 49
##STR00245## 50 ##STR00246## 51 ##STR00247##
TABLE-US-00064 TABLE 64 Ex Structure 52 ##STR00248## 53
##STR00249## 54 ##STR00250## 55 ##STR00251##
TABLE-US-00065 TABLE 65 Ex Structure 56 ##STR00252## 57
##STR00253## 58 ##STR00254## 59 ##STR00255##
TABLE-US-00066 TABLE 66 Ex Structure 60 ##STR00256## 61
##STR00257## 62 ##STR00258## 63 ##STR00259##
TABLE-US-00067 TABLE 67 Ex Structure 64 ##STR00260## 65
##STR00261## 66 ##STR00262## 67 ##STR00263##
TABLE-US-00068 TABLE 68 Ex Structure 68 ##STR00264## 69
##STR00265## 70 ##STR00266## 71 ##STR00267##
TABLE-US-00069 TABLE 69 Ex Structure 72 ##STR00268## 73
##STR00269## 74 ##STR00270## 75 ##STR00271##
TABLE-US-00070 TABLE 70 Ex Structure 76 ##STR00272## 77
##STR00273## 78 ##STR00274## 79 ##STR00275##
TABLE-US-00071 TABLE 71 Ex Structure 80 ##STR00276## 81
##STR00277## 82 ##STR00278## 83 ##STR00279##
TABLE-US-00072 TABLE 72 Ex Structure 84 ##STR00280## 85
##STR00281## 86 ##STR00282## 87 ##STR00283##
TABLE-US-00073 TABLE 73 Ex Structure 88 ##STR00284## 89
##STR00285## 90 ##STR00286## 91 ##STR00287##
TABLE-US-00074 TABLE 74 Ex Structure 92 ##STR00288## 93
##STR00289## 94 ##STR00290## 95 ##STR00291##
TABLE-US-00075 TABLE 75 Ex Structure 96 ##STR00292## 97
##STR00293## 98 ##STR00294## 99 ##STR00295##
TABLE-US-00076 TABLE 76 Ex Structure 100 ##STR00296## 101
##STR00297## 102 ##STR00298## 103 ##STR00299##
TABLE-US-00077 TABLE 77 Ex Structure 104 ##STR00300## 105
##STR00301## 106 ##STR00302##
TABLE-US-00078 TABLE 78 Ex Structure 107 ##STR00303## 108
##STR00304## 109 ##STR00305## 110 ##STR00306##
TABLE-US-00079 TABLE 79 Ex Structure 111 ##STR00307## 112
##STR00308## 113 ##STR00309## 114 ##STR00310##
TABLE-US-00080 TABLE 80 Ex Structure 115 ##STR00311## 116
##STR00312## 117 ##STR00313## 118 ##STR00314##
TABLE-US-00081 TABLE 81 Ex Structure 119 ##STR00315## 120
##STR00316## 121 ##STR00317## 122 ##STR00318##
TABLE-US-00082 TABLE 82 Ex Structure 123 ##STR00319## 124
##STR00320## 125 ##STR00321## 126 ##STR00322##
TABLE-US-00083 TABLE 83 Ex Structure 127 ##STR00323## 128
##STR00324## 129 ##STR00325## 130 ##STR00326##
TABLE-US-00084 TABLE 84 Ex Structure 131 ##STR00327## 132
##STR00328## 133 ##STR00329## 134 ##STR00330##
TABLE-US-00085 TABLE 85 Ex Structure 135 ##STR00331## 136
##STR00332## 137 ##STR00333## 138 ##STR00334##
TABLE-US-00086 TABLE 86 Ex Structure 139 ##STR00335## 140
##STR00336## 141 ##STR00337## 142 ##STR00338##
TABLE-US-00087 TABLE 87 Ex Structure 143 ##STR00339## 144
##STR00340## 145 ##STR00341## 146 ##STR00342##
TABLE-US-00088 TABLE 88 Ex Structure 147 ##STR00343## 148
##STR00344## 149 ##STR00345## 150 ##STR00346##
TABLE-US-00089 TABLE 89 Ex Structure 151 ##STR00347## 152
##STR00348## 153 ##STR00349## 154 ##STR00350##
TABLE-US-00090 TABLE 90 Ex Structure 155 ##STR00351## 156
##STR00352## 157 ##STR00353## 158 ##STR00354##
TABLE-US-00091 TABLE 91 Ex Structure 159 ##STR00355## 160
##STR00356## 161 ##STR00357## 162 ##STR00358##
TABLE-US-00092 TABLE 92 Ex Structure 163 ##STR00359## 164
##STR00360## 165 ##STR00361## 166 ##STR00362##
TABLE-US-00093 TABLE 93 Ex Structure 167 ##STR00363## 168
##STR00364## 169 ##STR00365## 170 ##STR00366##
TABLE-US-00094 TABLE 94 Ex Structure 171 ##STR00367## 172
##STR00368## 173 ##STR00369## 174 ##STR00370##
TABLE-US-00095 TABLE 95 Ex Structure 175 ##STR00371## 176
##STR00372## 177 ##STR00373##
TABLE-US-00096 TABLE 96 PEx PSyn Data 1 1 ESI+: 379 2 2 ESI+: 412 3
3 ESI+: 494 4 4 FAB-: 238 5 5 ESI+: 319 6 6 NMR2: 1.53(9H, s),
3.90(3H, s), 5.10(2H, s), 6.58(1H, brs), 7.20-7.56(8H, m) 7 7 ESI+:
412 8 8 EI: 322 9 9 FAB+: 423 10 10 EI: 322 11 11 ESI+: 365 12 12
ESI+: 238 13 13 ESI+: 493 14 14 ESI+: 397 15 15 ESI+: 411 16 16
ESI+: 511 17 17 ESI+: 493 18 18 NMR1: 1.31(3H, t, J = 7.1 Hz),
4.32(2H, q, J = 7.1 Hz), 7.35(2H, bs), 8.99(1H, s), 9.42(1H, s) 19
19 ESI+: 255, 257 20 20 ESI+: 422 21 21 ESI+: 408 22 22 ESI+: 522
23 23 ESI+: 432 24 24 ESI+: 635 25 25 ESI+: 439 26 26 ESI+: 398 27
27 ESI+: 512 28 28 ESI+: 412 29 29 ESI+: 383 30 30 ESI+: 479 31 31
ESI+: 256 32 32 ESI+: 156 33 33 EI: 223 34 34 ESI+: 223 35 35 NMR2:
0.47(2H, m), 0.58(2H, m), 1.13(1H, m), 1.32(6H, d), 2.97(2H, d),
3.87(3H, s), 4.56(1H, m), 6.58-6.67(3H, m), 6.88-6.93(2H, m),
7.12(1H, m), 7.21(1H, m) 36 36 ESI+: 398 37 37 ESI+: 384
TABLE-US-00097 TABLE 97 PEx PSyn Data 38 38 NMR2: 3.82(3H, s),
6.83(1H, dd, J = 2.4, 2.4 Hz), 7.07(1H, dd, J = 2.4, 2.4 Hz),
7.20(2H, d, J = 9.2 Hz), 7.27(1H, dd, J = 2.4, 2.4 Hz), 8.27(2H,
d), 10.36(1H, br) 39 39 ESI+: 478 40 40 ESI+: 448 41 41 APCI/ESI+:
390 42 42 NMR2: 1.32(6H, d, J = 6.0 Hz), 1.52(9H, s), 3.87(3H, s),
4.56(1 H, m), 6.47(1H, brs), 6.68(1H, m), 6.97(2H, m), 7.16(1H, m),
7.26(1H, m), 7.35(2H, m) 43 43 NMR2: 0.11-0.17(2H, m),
0.41-0.48(2H, m), 0.85-0.89(1H, m), 1.33(6H, d, J = 6.0 Hz),
1.44(9H, s), 3.48(2H, d, J = 7.0 Hz), 3.87(3H, s), 4.55(1H, m),
6.72-6.74(1H, m), 6.96-6.99(2H, m), 7.18-7.22(1H, m), 7.25-7.27(1H,
m), 7.29-7.31(2H, m) 44 44 ESI+: 478 45 45 ESI+: 446 46 46 ESI+:
454 47 47 ESI+: 440 48 48 ESI+: 554 49 49 ESI+: 424 50 50 ESI+: 579
51 51 ESI+: 464 52 52 ESI+: 366, 368 53 53 ESI+: 333 54 54 ESI+:
304(-Boc) 55 55 ESI+: 400 56 56 NMR2: 0.06-0.12(2H, m), 0.47(2H,
m), 0.88-0.96(1H, m), 1.10(6H, d, J = 6.6 Hz), 1.37(6H, d, J = 6.0
Hz), 2.44(1H, m), 3.67(2 H, d, J = 7.0 Hz), 3.91(3H, s),
4.58-4.67(1H, m), 6.92-6.94(1H, m), 7.42-7.44(1H, m), 7.46-7.48(1H,
m), 8.08(1H, d, J = 1.3 Hz), 8.33(1H, d, J = 1.3 Hz) 57 57 NMR2:
0.05-0.12(2H, m), 0.40-0.48(2H, m), 0.95-0.99(1H, m), 1.11(6H, d, J
= 6.6 Hz), 1.39(6H, d, J = 6.0 Hz), 1.65(9H, s), 2.44-2.47(1H, m),
3.69(2H, d, J = 7.1 Hz), 4.59-4.69(1H, m), 6.90-6.96(1H, m),
7.11(1H, d, J = 2.9 Hz), 7.23-7.26(1H, m), 7.27- 7.31(1H, m),
8.03(1H, d, J = 2.9 Hz), 8.09(1H, br), 8.38(1H, br), 8.62(1H, br)
58 58 FAB+: 380 59 59 ESI+: 356 60 60 ESI+: 448 61 61 ESI+: 479 62
62 ESI+: 353, 355 63 63 ESI+: 364, 366
TABLE-US-00098 TABLE 98 PEx PSyn Data 64 64 ESI+: 414 65 65 ESI+:
437 66 66 ESI+: 416 67 67 ESI+: 330 68 68 NMR2: 0.23(2H, m),
0.55(2H, m), 1.04(1H, m), 2.96(2H, d), 3.89(3H, s), 5.06(2H, s),
6.40(1H, m), 6.92(1H, m), 7.00(1H, m), 7.30-7.50(5H, m) 69 69 CI+:
354 70 70 EI: 263 71 71 ESI+: 509 72 72 ESI+: 498 73 73 ESI+: 470
74 74 ESI+: 453 75 75 ESI+: 651 76 76 ESI+: 303(-Boc) 77 77 NMR2:
0.21-0.24(2H, m), 0.40-0.45(2H, m), 1.13-1.19(1H, m), 1.34(6H, d, J
= 6.0 Hz), 1.52(9H, s), 3.81(2H, d, J = 7.0 Hz), 4.55-4.62(1H, m),
6.75-6.77(1H, m), 7.26-7.27(1H, m), 7.31- 7.36(2H, m),
7.60-7.62(1H, m), 8.17-8.18(1H, m) 78 78 ESI+: 366 79 79 ESI+: 467
80 52 ESI+: 333(-tBu) 81 49 NMR2: 0.25-0.34(2H, m), 0.54-0.62(2H,
m), 1.06-1.15(1H, m), 3.17(2H, brd, J = 6.8 Hz), 3.87(3H, s),
4.69(1H, br), 6.13(1 H, br), 6.72-6.74(1H, m), 7.06-7.08(1H, m),
7.20-7.24(1H, m), 7.55(1H, d, J = 1.3 Hz), 7.91(1H, d, J = 1.3 Hz)
82 35 ESI+: 502 83 36 NMR2: 1.32(6H, d, J = 6.1 Hz), 2.19(3H, s),
3.87(3H, s), 4.57(1 H, m), 6.69-6.71(1H, m), 6.97-7.01(2H, m),
7.16-7.18(1H, m), 7.25-7.27(1H, m), 7.46-7.50(2H, m) 84 36 ESI+:
544 85 37 ESI+: 530 86 37 ESI-: 374 87 37 ESI-: 440 88 39 ESI+: 362
89 40 ESI+: 332 90 35 ESI+: 386 91 40 ESI+: 336, 338 92 36 ESI+:
428 93 37 ESI+: 414 94 37 ESI+: 450 95 35 ESI+: 390
TABLE-US-00099 TABLE 99 PEx PSyn Data 96 36 ESI+: 432, 434 97 37
ESI+: 418 98 50 ESI+: 615 99 43 NMR2: 0.23-0.27(2H, m),
0.42-0.49(2H, m), 1.10-1.19(1H, m), 1.37(6H, d, J = 6.0 Hz),
1.52(9H, s), 3.78(2H, d, J = 7.0 Hz), 3.91(3H, s), 4.61(1H, m),
6.88-6.90(1H, m), 7.36-7.38(1H, m), 7.42-7.44(1H, m), 8.17(1H, d, J
= 1.3 Hz), 8.47(1H, d, J = 1.3 Hz) 100 49 NMR2: 0.26-0.30(2H, m),
0.56-0.61(2H, m), 1.08-1.16(1H, m), 1.35(6H, d, J = 6.0 Hz),
3.10-3.20(2H, m), 3.89(3H, s), 4.59 (1H, m), 4.65(1H, br),
6.77-6.79(1H, m), 7.19-7.21(1H, m), 7.31-7.33(1H, m), 7.57(1H, d, J
= 1.3 Hz), 7.95(1H, d, J = 1.3 Hz) 101 50 ESI+: 583, 585 102 37
ESI-: 384 103 37 NMR2: 0.98-0.13(2H, m), 0.43-0.50(2H, m),
0.94-1.00(1H, m), 1.13(6H, d, J = 6.6 Hz), 1.41(6H, d, J = 6.0 Hz),
1.86-1.92(1 H, m), 2.45(1H, br), 3.71(2H, d, J = 7.0 Hz),
4.62-4.69(1H, m), 7.00-7.02(1H, m), 7.51-7.53(1H, m), 7.53-7.55(1H,
m), 8.12 (1H, br), 8.39(1H, br) 104 9 FAB+: 324 105 4 ESI+: 351 106
5 ESI+: 430 107 40 ESI+: 350 108 2 ESI+: 463 109 56 ESI+: 442 110
37 ESI+: 428 111 3 ESI+: 545 112 5 ESI+: 423 113 2 ESI+: 352 114 3
ESI+: 434 115 37 ESI+: 434 116 37 ESI+: 344 117 5 ESI+: 218 118 9
ESI+: 353 119 2 ESI+: 386 120 3 ESI+: 468 121 5 ESI+: 296 122 53
ESI+: 381 123 54 ESI+: 452 124 63 ESI+: 506 125 9 ESI+: 397 126 9
ESI+: 321 127 2 ESI+: 354 128 3 ESI+: 436
TABLE-US-00100 TABLE 100 PEx PSyn Data 129 2 ESI+: 430 130 3 ESI+:
512 131 54 ESI+: 424, 426 132 43 ESI+: 478, 480 133 5 ESI+: 252 134
5 ESI+: 443, 445 135 9 ESI+: 355 136 2 ESI+: 388 137 9 ESI+: 378
138 3 ESI+: 470 139 9 ESI+: 442 140 53 ESI+: 386 141 54 ESI-: 455
142 63 ESI+: 511 143 37 ESI+: 397 144 5 ESI+: 476 145 2 ESI+: 411
146 3 ESI+: 493 147 63 ESI+: 300 148 63 ESI+: 392 149 5 ESI+: 379
150 63 ESI+: 316 151 5 ESI+: 471 152 5 ESI+: 395 153 5 ESI+: 409
154 49 ESI+: 411 155 37 ESI+: 484 156 9 ESI+: 408 157 2 ESI+: 444
158 3 NMR2: 1.32(3H, d), 1.97-2.07(2H, m), 2.35-2.41(3H, t), 2.85
(3H, s), 3.41(3H, s), 3.47-3.61(2H, m), 3.81(3H, s), 4.08-4.16 (2H,
m), 4.55-4.67(1H, m), 6.78(1H, m), 6.83 (1H, m), 7.13(1 H, m),
7.25-7.32(1H, m), 7.42(1H, dd), 8.18(1H, d), 8.38(1H, brs),
8.62(1H, d) 159 73 ESI+: 500 160 9 ESI+: 494 161 9 ESI+: 650 162 9
ESI-: 345 163 39 ESI+: 530 164 9 NMR2: 1.35(3H, d), 1.48(3H, t),
3.42(3H, s), 3.50-3.65 (2H, m), 3.82(3H, s), 4.51-4.70(3H, m),
6.80(1H, d), 6.98 (1H, m), 7.28(2H, m), 7.49(1H, m), 8.38(1H, brs),
8.63(1H, s), 9.05(1H, d) 165 9 ESI+: 411
TABLE-US-00101 TABLE 101 PEx PSyn Data 166 39 ESI+: 386 167 39
ESI+: 394(-Boc) 168 52 NMR2: 1.35(6H, d, J = 6.1 Hz), 1.64(9H, s),
3.89(3H, s), 4.55- 4.63(1H, m), 6.77-6.78(1H, m), 7.24-7.25(1H, m),
7.31-7.35(1 H, m), 7.39-7.41(1H, m), 8.03-8.06(1H, m),
8.49-8.50(1H, m) 169 9 NMR2: 1.61(9H, s), 3.89(3H, s),
6.72-6.73(1H, m), 7.26-7.42 (3H, m), 8.06-8.08(1H, m),
8.28-8.29(1H, m) 170 37 ESI+: 516 171 5 ESI+: 595 172 49 ESI+: 366
173 37 ESI+: 352 174 5 ESI+: 431 175 9 ESI+: 454 176 49 ESI+: 394
177 37 ESI+: 380 178 5 ESI+: 459 179 49 ESI+: 386 180 37 ESI+: 372
181 5 ESI+: 451 182 39 ESI+: 380(-Boc) 183 49 ESI+: 380 184 37
ESI+: 366 185 5 ESI+: 445 186 49 NMR2: 0.25-0.29(2H, m),
0.54-0.59(2H, m), 1.10-1.13(1H, m), 1.33(6H, d, J = 6.0 Hz),
3.11-3.14(2H, m), 3.80(3H, s), 4.54- 4.64(2H, m), 6.39-6.42(1H, m),
6.62-6.63(1H, m), 6.78-6.79 (1H, m), 6.88-6.89(1H, m),
7.06-7.07(1H, m), 7.17-7.20(1H, m), 7.27-7.28(1H, m), 7.93-7.94(1H,
m), 8.35(1H, brs) 187 9 NMR2: 1.33(3H, d, J = 6.2 Hz), 1.48(3H, t,
J = 7.2 Hz), 3.74-3.80 (5H, m), 4.52-4.61(3H, m), 6.79-6.80(1H, m),
6.96-6.97(1H, m), 7.29-7.30(2H, m), 7.39-7.40(1H, m), 8.48(1H, bs),
8.64(1 H, d, J = 1.3 Hz), 9.05(1H, d, J = 1.3 Hz) 188 9 ESI+: 529
189 9 NMR2: 1.33(3H, d, J = 6.3 Hz), 1.47(3H, t, J = 7.2 Hz),
3.40(3H, s), 3.44-3.67(2H, m), 3.82(3H, s), 4.46-4.71(3H, m),
6.79(1 H, m), 6.86(1H, m), 7.16(1H, m), 7.22-7.37(2H, m), 7.42(1H,
dd, J = 5.7, 8.7 Hz), 8.32(1H, d, J = 8.7 Hz), 8.50-8.65(2H, m) 190
49 ESI+: 388 191 57 ESI+: 674 192 50 ESI+: 649 193 5 NMR2:
0.22-0.27(2H, m), 0.40-0.46(2H, m), 1.14-1.20(1H, m), 1.34(6H, d, J
= 6.1 Hz), 1.52(9H, s), 3.80-3.83(5H, m), 4.53- 4.61(1H, m),
6.67-6.69(1H, m), 6.78-6.79(1H, m), 7.02-7.03 (1H, m),
7.14-7.15(1H, m), 7.26-7.35(2H, m), 7.60-7.63(1H, m), 8.17-8.18(1H,
m), 8.39(1H, brs)
TABLE-US-00102 TABLE 102 Ex Syn Data 1 1 NMR2: 1.26(3H, d, J = 6.4
Hz), 3.30(3H, s), 3.45-3.56(2H, m), 3.77(3H, s), 4.75-4.83(1H, m),
6.57(1H, d, J = 2.4 Hz), 7.04(1H, t, J = 2.4 Hz), 7.34-7.40(1H, m),
7.50-7.54(1H, m), 7.60(1H, d, J = 2.4 Hz), 7.69(1H, dd, J = 3.2,
8.8 Hz), 8.18(1H, brs), 8.31(1H, d, J = 8.8 Hz), 8.44(1H, brs),
8.69(1H, d, J = 3.2 Hz) ESI+: 494 2 2 NMR1: 1.31(6H, d, J = 6.0
Hz), 2.82(3H, d, J = 4.7 Hz), 3.77(3H, s), 4.73-4.80(1H, m),
6.57(1H, d, J = 2.2 Hz), 6.99-7.01(1H, m), 7.35- 7.37(1H, m),
7.48-7.50(1H, m), 7.60(1H, d, J = 2.2 Hz), 7.68(1H, dd, J = 2.8,
8.7 Hz), 8.30(1H, d, J = 8.6 Hz), 8.69(1H, d, J = 2.9 Hz),
9.02-9.07(1H, m), 10.88(1H, s) ESI+: 478 3 3 NMR1: 1.31(6H, d, J =
6.0 Hz), 2.83(3H, br), 3.77(3H, s), 4.77(1H, m), 6.57(1H, d, J =
2.3 Hz), 6.98(1H, dd, J = 2.2, 2.2 Hz), 7.34(1H, br), 7.47(1H, br),
7.60(1H, d, J = 2.3 Hz), 7.67(1H, dd, J = 8.8, 2.8 Hz), 8.27(1H, d,
J = 8.8 Hz), 8.66(1H, d, J = 2.8 Hz), 9.31(1H, br), 10.89 (1H, s)
ESI+: 478 4 4 ESI+: 534 5 5 ESI+: 445 6 6 ESI+: 426 7 7 NMR2:
1.31(3H, d, J = 6.4 Hz), 2.33(1H, t, J = 4.8 Hz), 3.08(3H, d, J =
4.8 Hz), 3.70-3.83(5H, m), 4.52-4.62(1H, m), 6.75-6.85(2H, m),
7.00-7.11(1H, m), 7.26-7.32(2H, m), 7.37-7.51(2H, m), 8.15 (1H, d,
J = 8.8 Hz), 8.57(1H, d, J = 2.8 Hz), 8.80(1H, brs) 8 8 ESI+: 467 9
9 NMR1: 1.32(3H, d, J = 6.0 Hz), 3.77(3H, s), 4.70-4.85(1H, m),
6.57(1H, m), 7.00(1H, m), 7.35(1H, m), 7.47(1H, m), 7.62(1H, m),
7.68(1H, m), 8.17(1H, brs), 8.30(1H, d, J = 8.8 Hz), 8.43(1H, brs),
8.67(1H, m) 10 10 NMR1: 1.31(6H, d, J = 6.0 Hz), 3.07(6H, s),
3.77(3H, s), 4.72-4.81 (1H, m), 6.57(1H, d, J = 2.2 Hz),
6.98-7.01(1H, m), 7.33-7.36(1H, m), 7.46-7.50(1H, m), 7.60(1H, d, J
= 2.2 Hz), 7.67(1H, dd, J = 2.8, 8.7 Hz), 8.31(1H, d, J = 8.8 Hz),
8.67(1H, d, J = 2.8 Hz), 10.88(1H, s) ESI+: 492 11 11 ESI+: 467 12
12 ESI+: 460 13 13 ESI+: 478 14 14 ESI+: 461 15 15 ESI+: 464 16 16
ESI+: 521
TABLE-US-00103 TABLE 103 Ex Syn Data 17 17 NMR1: 1.56-1.86(2H, m),
2.17-2.33(4H, m), 2.83(3H, d, J = 4.7 Hz), 3.69-3.79(5H, m),
4.98(1H, t, J = 5.6 Hz), 6.56(1H, d, J = 2.2 Hz), 6.88-6.91(1H, m),
7.31-7.35(1H, m), 7.40-7.44(1H, m), 7.60(1 H, d, J = 2.2 Hz),
7.65-7.71(1H, m), 8.29-8.33(1H, m), 8.68(1H, d, J = 2.8 Hz),
9.01-9.08(1H, m), 10.85(1H, s) ESI+: 520 18 18 NMR1: 1.31(6H, d, J
= 6.0 Hz), 2.84(3H, d, J = 4.7 Hz), 3.78(3H, s), 4.71-4.80(1H, m),
6.58(1H, d, J = 2.2 Hz), 7.08-7.10(1H, m), 7.45- 7.47(1H, m),
7.50-7.53(1H, m), 7.60(1H, d, J = 2.2 Hz), 8.80(1H, d, J = 1.3 Hz),
9.01(1H, d, J = 1.4 Hz), 9.30-9.36(1H, m), 10.86(1H, s) ESI+: 479
19 19 ESI+: 508 20 20 ESI+: 466 21 21 ESI+: 480 22 22 ESI+: 518 23
23 ESI+: 535 24 24 NMR2: 0.08-0.13(2H, m), 0.42-0.48(2H, m),
0.90-0.99(1H, m), 1.33(3H, d, J = 6.2 Hz), 1.60-1.64(1H, m),
1.88-2.01(2H, m), 2.02- 2.07(1H, m), 2.41(1H, m), 3.20-3.31(2H, m),
3.68(2H, d, J = 7.1 Hz), 3.73-3.82(2H, m), 3.82(3H, s),
3.92-3.96(2H, m), 4.52-4.57(1 H,m), 6.79-6.18(1H, d, J = 2.2 Hz),
6.96-6.99(1H, m), 7.29-7.32(2 H, m), 7.36-7.38(1H, m), 8.01(1H,
br), 8.37(1H, br), 8.49(1H, br) ESI+: 551 25 25 ESI+: 479 26 26
ESI+: 522 27 27 APCI/ESI+: 518 28 28 ESI+: 465 29 29 NMR2:
0.11-0.17(2H, m), 0.42-0.49(2H, m), 0.95-1.03(1H, m), 1.35(3H, d, J
= 6.3 Hz), 2.20(6H, s), 3.05(2H, s), 3.41(3H, s), 3.51(1 H, dd, J =
4.1, 10.4 Hz), 3.60(1H, dd, J = 6.0, 10.4 Hz), 3.73(2H, d, J = 7.1
Hz), 3.82(3H, s), 4.62(1H, ddq, J = 4.1, 6.0, 6.3 Hz), 6.80(1H, d,
J = 2.3 Hz), 6.94-6.97(1H, m), 7.26-7.28(1H, m), 7.29(1H, d, J =
2.3 Hz), 7.34-7.36(1H, m), 8.14(1H, br), 8.30(1H, d, J = 1.3 Hz),
8.49 (1H, br) ESI+: 538 30 30 APCI/ESI+: 526 31 31 ESI+: 482 32 32
ESI+: 495 33 33 ESI+: 490 34 34 ESI+: 504 35 35 ESI+: 556 36 36
ESI+: 492 37 37 ESI+: 563 38 38 ESI+: 493
TABLE-US-00104 TABLE 104 Ex Syn Data 39 39 ESI+: 521 40 40 ESI+:
524 41 20 ESI+: 612 42 20 ESI+: 609 43 24 ESI+: 508 44 24 ESI+: 505
45 20 ESI+: 458 46 26 ESI+: 519 47 20 ESI+: 524 48 21 ESI+: 502 49
21 ESI+: 496 50 21 ESI+: 492 51 21 ESI+: 494 52 21 ESI+: 482 53 21
ESI+: 524 54 20 ESI+: 463 55 20 ESI+: 566 56 20 ESI+: 481 57 29
ESI+: 509 58 20 ESI+: 493 59 20 ESI+: 529 60 25 ESI+: 515 61 28
ESI+: 501 62 25 ESI+: 483, 485 63 20 ESI+: 465 64 20 ESI+: 493 65
25 ESI+: 479 66 22 ESI+: 507 67 2 NMR2: 1.38(6H, d, J = 6.0 Hz),
3.20(3H, s), 3.31(3H, s), 3.81(3H, s), 4.58-4.66(1H, m), 6.80(1H,
brd, J = 2 Hz), 6.90(1H, t, 2.4 Hz), 7.24-7.26(1H, m), 7.29(1H,
brd, J = 2.4 Hz), 7.31-7.33(1H, m), 8.41 (1H, brs), 8.61(1H, d, J =
1.2 Hz), 8.91(1H, d, J = 1.2 Hz) ESI+: 493 68 1 ESI+: 465 69 2
ESI+: 433 70 1 ESI+: 516 71 2 ESI+: 544 72 22 ESI+: 533 73 22 ESI+:
528 74 22 ESI+: 535 75 22 ESI+: 528 76 22 ESI+: 523 77 22 ESI+:
479
TABLE-US-00105 TABLE 105 Ex Syn Data 78 22 ESI+: 495 79 20 ESI+:
513 80 22 ESI+: 481 81 22 ESI+: 491 82 29 ESI+: 508 83 2 ESI+: 467
84 1 ESI+: 405 85 5 ESI+: 459 86 5 ESI+: 419 87 22 ESI+: 493 88 22
ESI+: 528 89 23 ESI+: 509 90 23 ESI+: 505 91 22 ESI+: 505 92 22
ESI+: 519 93 2 ESI+: 435 94 23 ESI+: 548 95 2 ESI+: 511 96 22 ESI+:
509 97 22 ESI+: 528 98 2 NMR1: 1.31(6H, d, J = 6.4 Hz), 3.09(3H,
s), 3.36(3H, s), 3.78(3H, s), 4.72-4.78(1H, m), 6.58(1H, d, J = 2.4
Hz), 7.09(1H, t, 2 Hz), 7.44-7.47(1H, m), 7.50-7.53(1H, m),
7.60(1H, d, J = 2.4 Hz), 8.81(1 H, d, J = 1.2 Hz), 9.01 (1H, d, J =
1.2 Hz), 10.86(1H, brs) ESI+: 493 99 2 ESI+: 469 100 23 ESI+: 555,
557 101 23 ESI+: 588 102 4 NMR1: 0.66-0.81(4H, m), 1.31(6H, d, J =
5.6 Hz), 2.89- 2.96(1H, m), 3.77(3H, s), 4.70-4.79(1H, m), 6.57(1H,
d, J = 2.4 Hz), 7.08(1 H, brt, J = 2 Hz), 7.45(1H, brt, J = 2 Hz),
7.51(1H, brt, J = 2 Hz), 7.60(1 H, d, J = 2.4 Hz), 8.78(1H, d, J =
1.2 Hz), 8.87 (1H, d, J = 1.2 Hz), 9.61 (1H, brs), 10.85(1H, brs)
ESI+: 505 103 22 ESI+: 532 104 22 ESI+: 532 105 22 ESI+: 532 106 23
ESI+: 529 107 23 ESI+: 534 108 23 ESI+: 534
TABLE-US-00106 TABLE 106 Ex Syn Data 109 2 NMR2: 1.36(6H, d, J =
6.0 Hz), 3.20(3H, s), 3.32(3H, s), 3.81(3H, s), 4.57-4.64(1H, m),
6.76-6.80(2H, m), 7.09-7.11(1H, m), 7.23- 7.25(1H, m), 7.29(1H, d,
J = 2.4 Hz), 7.43(1H, d, J = 2.8 Hz), 7.45(1 H, d, J = 2.8 Hz),
8.14(1H, d, J = 1 Hz), 8.16(1H, d, J = 1 Hz), 8.40(1H, brs),
8.61(1H, d, J = 2.8 Hz) ESI+: 492 110 23 ESI+: 521 111 23 ESI+: 521
112 23 ESI+: 521 113 23 ESI+: 491 114 25 ESI+: 574 115 23 ESI+: 507
116 23 NMR1: 0.00-0.15(2H, m), 0.28-0.45(2H, m), 0.80-1.00(1H, m),
1.36(3H, t, J = 7.0 Hz), 1.47-1.73(4H, m), 3.07-3.42(3H, m), 3.60
(2H, d, J = 7.0 Hz), 3.72-3.84(5H, m), 4.14(2H, q, J = 7.0 Hz),
6.58(1 H, d, J = 2.3 Hz), 7.05(1H, s), 7.44(1H, s), 7.51(1H, s),
7.61(1H, d, J = 2.3 Hz), 8.34(1H, s), 8.53(1H, s), 10.88(1H, s)
ESI+: 521 117 4 NMR1: 0.65-0.76(4H, m), 1.31(6H, d, J = 6.0 Hz),
2.87-2.95(1H, m), 3.77(3H, s), 4.72-4.81(1H, m), 6.57(1H, d, J =
2.3 Hz), 6.99- 7.01(1H, m) 7.34-7.38(1H, m), 7.47-7.50(1H, m),
7.60(1H, d, J = 2.2 Hz), 7.67(1H, dd, J = 2.9, 8.8 Hz), 8.31(1H, d,
J = 8.8 Hz), 8.68(1H, d, J = 2.9 Hz), 9.15-9.18(1H, m), 10.88(1H,
s) ESI+: 504 118 23 NMR1: 0.00-0.08(2H, m), 0.28-0.41(2H, m),
0.80-1.00(1H, m), 1.47-1.70(4H, m), 3.09-3.46(3H, m), 3.60(2H, d, J
= 7.6 Hz), 3.72- 3.80(5H, m), 5.22(2H, s), 6.58(1H, d, J = 2.3 Hz),
7.16(1H, dd, J = 2.2, 2.2 Hz), 7.32-7.52(6H, m), 7.61(1H, d, J =
2.3 Hz), 7.64(1H, dd, J = 1.9, 1.9 Hz), 8.34(1H, d, J = 1.2 Hz),
8.53(1H, d, J = 1.2 Hz), 10.90 (1H, s) ESI+: 583 119 23 ESI+: 539
120 25 ESI+: 549 121 2 NMR1: 1.30(6H, d, J = 6.0 Hz), 2.82-2.86(3H,
m), 3.78(3H, s), 4.72-4.80(1H, m), 6.57(1H, d, J = 2.2 Hz),
6.95-6.98(1H, m), 7.32- 7.34(1H, m), 7.45-7.48(1H, m), 7.60(1H, d,
J = 2.3 Hz), 7.67(1H, dd, J = 2.9, 8.7 Hz), 8.16(1H, d, J = 8.7
Hz), 8.64(1H, d, J = 2.9 Hz), 9.46(1 H, brs), 10.88(1H, brs) ESI+:
478
TABLE-US-00107 TABLE 107 Ex Syn Data 122 4 NMR1: 0.68-0.80(4H, m),
1.30(6H, d, J = 6.0 Hz), 2.89-2.96(1H, m), 3.77(3H, s),
4.71-4.81(1H, m), 6.56(1H, d, J = 2.2 Hz), 6.95- 6.98(1H, m),
7.30-7.34(1H, m), 7.44-7.48(1H, m), 7.60(1H, d, J = 2.3 Hz),
7.66(1H, dd, J = 2.9, 8.7 Hz), 8.16(1H, d, J = 8.7 Hz), 8.63(1H, d,
J = 2.8 Hz), 9.59(1H, br), 10.87(1H, s) ESI+: 504 123 4 ESI+: 534
124 6 NMR1: 1.30(6H, d, J = 6.0 Hz), 3.77(3H, s), 4.62-4.67(2H, m),
4.72-4.81(1H, m), 5.78(1H, br), 6.57(1H, d, J = 2.2 Hz),
6.98-7.00(1 H, m), 7.34-7.36(1H, m), 7.46-7.49(1H, m), 7.60(1H, d,
J = 2.2 Hz), 7.64(1H, dd, J = 2.8, 8.7 Hz), 8.26(1H, d, J = 8.7
Hz), 8.66(1H, d, J = 2.8 Hz), 10.88(1H, s) ESI+: 451 125 28 ESI+:
549 126 28 ESI+: 535 127 23 ESI+: 565 128 4 NMR1: 1.31(6H, d, J =
6.0 Hz), 3.27-3.41(2H, m), 3.51-3.57(2H, m), 3.77(3H, s),
4.73-4.82(2H, m), 6.57(1H, d, J = 2.2 Hz), 6.99- 7.02(1H, m),
7.35-7.38(1H, m), 7.47-7.50(1H, m), 7.60(1H, d, J = 2.2 Hz),
7.68(1H, dd, J = 2.9, 8.8 Hz), 8.32(1H, d, J = 8.7 Hz), 8.69(1H, d,
J = 2.9 Hz), 8.92-8.98(1H, m), 10.88(1H, s) ESI+: 508 129 2 NMR2:
1.33(3H, d, J = 6.4 Hz), 3.08(3H, d, J = 5.6 Hz), 3.40(3H, s),
3.48-3.61(2H, m), 3.78(3H, s), 4.56-4.64(1H, m), 6.79(1H, d, J =
2.0 Hz), 6.84(1H, t, J = 2.0 Hz), 7.09-7.13(1H, m, J = 1.6 Hz),
7.26- 7.32(2H, m), 7.35-7.46(2H, m), 8.16(1H, d, J = 8.4 Hz),
8.55(1H, brs), 8.59(1H, d, J = 2.4 Hz) APCI/ESI+: 508 130 2 NMR2:
1.33(3H, d, J = 6.4 Hz), 3.20(3H, s), 3.32(3H, s), 3.40(3H, s),
3.47-3.61(2H, m), 3.79(3H, s), 4.56-4.64(1H, m), 6.78(1H, d, J =
2.0 Hz), 6.82-6.86(1H, m), 7.11-7.15(1H, m), 7.26-7.33(2H, m),
7.43(1H, dd, J = 3.2, 8.8 Hz), 8.12-8.17(1H, m), 8.49(1H, brs),
8.58-8.63(1H, m) ESI+: 522 131 4 ESI+: 508 132 23 ESI+: 551 133 23
ESI+: 551 134 23 ESI+: 569 135 1 ESI+: 494 136 23 ESI+: 539 137 7
ESI+: 520
TABLE-US-00108 TABLE 108 Ex Syn Data 138 2 NMR1: 1.31(6H, d, J =
6.0 Hz), 2.82(3H, d, J = 4.7 Hz), 3.78(3H, s), 4.75(1H, m),
6.58(1H, d, J = 2.3 Hz), 7.10(1H, dd, J = 2.2, 2.2 Hz), 7.47(1H,
dd, J = 2.2, 2.2 Hz), 7.52(1H, dd, J = 2.2, 2.2 Hz), 7.61(1H, d, J
= 2.3 Hz), 8.84(1H, d, J = 1.3 Hz), 9.04(1H, d, J = 1.3 Hz),
9.08(1H, q, J = 4.7 Hz), 10.88(1H, s) ESI+: 479 139 2 NMR1:
1.14(3H.t.J = 7.1 Hz), 1.31(6H, d, J = 6.0 Hz), 3.26-3.45(2 H, m),
3.78(3H, s), 4.75(1H, m), 6.58(1H, d, J = 2.3 Hz), 7.10(1H, dd, J =
2.2, 2.2 Hz), 7.47(1H, dd, J = 2.2, 2.2 Hz), 7.52(1H, dd, J = 2.2,
2.2 Hz), 7.61(1H, d, J = 2.3 Hz), 8.84(1H, d, J = 1.3 Hz), 9.04(1H,
d, J = 1.3 Hz), 9.16(1H, t, J = 5.7 Hz), 10.88(1H, s) ESI+: 493 140
1 ESI+: 465 141 25 ESI+: 551 142 23 ESI+: 557 143 2 NMR1: 1.26(3H,
d, J = 6.1 Hz), 2.82(3H, d, J = 4.3 Hz), 3. 30(3H, s),
3.45-3.60(2H, m), 3.78(3H, s), 4.74-4.83(1H, m), 6.58(1H, d, J =
2.2 Hz), 7.14(1H, s), 7.47(1H, s), 7.56(1H, s), 7.61(1H, d, J = 2.2
Hz), 8.84(1H, d, J = 1.2 Hz), 9.04(1H, d, J = 1.2 Hz), 9.09(1H, q,
J = 4.3 Hz), 10.89(1H, s) ESI+: 509 144 23 ESI+: 563 145 2 NMR2:
1.26-1.38(6H, m), 3.41(3H, s), 3.48-3.64(4H, m), 3.76(3 H, s),
4.57-4.65(1H, m), 6.80(1H, d, J = 2.0 Hz), 6.95-6.98(1H, m),
7.14-7.20(1H, m), 7.25-7.32(2H, m), 7.38-7.42(1H, m), 8.62(1 H, d,
J = 1.6 Hz), 8.83(1H, brs), 8.99(1H, d, J = 1.2 Hz) ESI+: 523 146 2
NMR1: 1.15(3H, t, 7.2 Hz), 1.31(6H, d, J = 6.0 Hz), 3.32(2H, m),
3.77(3H, s), 4.77(1H, m), 6.57(1H, d, J = 2.3 Hz), 6.98(1H, dd, J =
2.2, 2.2 Hz), 7.34(1H, dd, J = 2.2, 2.2 Hz), 7.47(1H, dd, J = 2.2,
2.2 Hz), 7.60(1H, d, J = 2.3 Hz), 7.67(1H, dd, J = 8.6, 2.8 Hz),
8.27(1H, d, J = 8.6 Hz), 8.67(1H, d, J = 2.8 Hz), 9.40(1H, d, 5.8
Hz), 10.89(1H, s) ESI+: 492 147 1 ESI+: 495 148 1 NMR1: 1.31(6H, d,
J = 6.0 Hz), 3.77(3H, s), 4.77(1H, m), 6.57(1H, d, J = 2.3 Hz),
6.98(1H, dd, J = 2.2, 2.2 Hz), 7.34(1H, dd, J = 2.2, 2.2 Hz),
7.47(1H, dd, J = 2.2, 2.2 Hz), 7.60(1H, d, J = 2.3 Hz), 7.67(1H,
dd, J = 8.6, 2.8 Hz), 8.27(1H, d, J = 8.6 Hz), 8.28(1H, br),
8.66(1H, d, J = 2.8 Hz), 8.70(1H, br), 10.89(1H, s) ESI+: 464
TABLE-US-00109 TABLE 109 Ex Syn Data 149 23 ESI+: 534 150 4 ESI+:
522 151 4 NMR1: 0.60-0.83(4H, m), 0.98-1.17(1H, m), 1.31(6H, d, J =
6.2 Hz), 3.77(3H, s), 4.77(1H, m), 6.57(1H, d, J = 2.3 Hz),
6.98(1H, s), 7.34(1H, s), 7.47(1H, s), 7.60(1H, d, J = 2.3 Hz),
7.67(1H, dd, J = 8.6, 2.8 Hz), 8.27(1H, d, J = 8.6 Hz), 8.67(1H, d,
J = 2.8 Hz), 9.47(1H, d, 3.4 Hz), 10.89(1H, s) ESI+: 504 152 23
ESI+: 571 153 23 ESI+: 543 154 2 NMR2: 1.33(3H, d, J = 6.0 Hz),
3.07(3H, d, J = 4.8 Hz), 3.40(3H, s), 3.48-3.62(2H, m), 3.78(3H,
s), 4.56-4.65(1H, m), 6.78(1H, d, J = 2.0 Hz), 6.84-6.88(1H, m),
7.12-7.36(5H, m), 8.25(1H, d, J = 8.8 Hz), 8.58-8.67(2H, m) ESI+:
508 155 7 NMR2: 1.31(3H, m, J = 6.4 Hz), 2.39(1H, t, J = 6.4 Hz),
3.07(3H, d, J = 5.2 Hz), 3.72-3.84(5H, m), 4.53-4.62(1H, m),
6.79(1H, d, J = 2.0 Hz), 6.82-6.86(1H, m), 7.11-7.15(1H, m),
7.21-7.35(4H, m), 7.42 (1H, dd, J = 2.8, 8.8 Hz), 8.24(1H, d, J =
8.8 Hz), 8.60(1H, d, J = 2.8 Hz), 8.76(1H, brs) ESI+: 494 156 24
ESI+: 555 157 29 ESI+: 536 158 24 ESI+: 537 159 24 ESI+: 525 160 2
NMR2: 1.23-1.38(6H, m), 3.40(3H, s), 3.48-3.64(2H, m), 3.80(3 H,
s), 4.57-4.65(1H, m), 6.78(1H, d, J = 2.0 Hz), 6.85-6.89(1H, m),
7.13-7.37(4H, m), 7.44(1H, dd, J = 3.2, 8.8 Hz), 8.26(1H, d, J =
8.8 Hz), 8.55-8.65(2H, m) ESI+: 522 161 7 ESI+: 508 162 7 ESI+: 480
163 2 ESI+: 464 164 1 ESI+: 450 165 2 ESI+: 478 166 22 ESI+: 518
167 2 ESI+: 495 168 2 NMR1: 1.14(3H, t, J = 7.2 Hz), 1.31(6H, d, J
= 6.0 Hz), 3.28-3.36(2 H, m), 3.77(3H, s), 4.73-4.80(1H, m),
6.57(1H, d, J = 2.3 Hz), 6.99- 7.02(1H, m), 7.35-7.38(1H, m),
7.48-7.50(1H, m), 7.60(1H, d, J = 2.3 Hz), 7.68(1H, dd, J = 2.8,
8.7 Hz), 8.31(1H, d, J = 8.8 Hz), 8.69(1 H, d, J = 2.9 Hz),
9.09-9.14(1H, m), 10.89(1H, s) ESI+: 492
TABLE-US-00110 TABLE 110 Ex Syn Data 169 24 ESI+: 534 170 2 NMR2:
3.07(3H, d, J = 5.2 Hz), 3.74(3H, s), 4.52-4.86(5H, m), 6.77(1H, d,
J = 2.0 Hz), 6.90-6.96(1H, m), 7.17-7.51 (5H, m), 8.24(1 H, d, J =
8.8 Hz), 8.59(1H, d, J = 2.8 Hz), 9.02(1H, brs) 171 2 NMR2:
1.28(3H, t, J = 7.2 Hz), 2.05(3H, d, J = 8.8 Hz), 3.48-3.62(2 H,
m), 3.70(3H, s), 4.47-4.89(5H, m), 6.72- 6.82(1H, m), 6.85-7.00(1H,
m), 7.20-7.33(2H, m), 7.34- 7.49(2H, m), 8.23(1H, d, J = 8.8 Hz),
8.58(1H, d, J = 2.8 Hz), 9.36(1H, brs) ESI+: 528 172 1 ESI+: 500
173 1 ESI+: 481 174 2 ESI+: 509 175 2 ESI+: 521 176 27 ESI+: 475
177 24 ESI+: 537
INDUSTRIAL APPLICABILITY
[0316] The compound of the formula (I) or a salt thereof has a GK
activating action, and can be used as an active ingredient of a
pharmaceutical composition for preventing and/or treating diabetes,
particularly type 2 diabetes mellitus. Further, it can be used as
an active ingredient of a pharmaceutical composition for preventing
and/or treating nephropathy, retinopathy, neuropathy, peripheral
circulatory disorder, cerebrovascular disorder, ischemic heart
disease, and arteriosclerosis that are complications of diabetes
mellitus. It can further be used as an active ingredient of a
pharmaceutical composition for preventing and/or treating obesity
or metabolic syndrome by suppressing overeating.
[0317] Sequence Listing Free Text
[0318] Under the number title <223> in the following sequence
listing, description of "Artificial Sequence" is provided.
Specifically, the base sequences as set forth as SEQ ID NO: 1 and 2
in the sequence listing are artificially synthesized primer
sequences.
Sequence CWU 1
1
2128DNAArtificialDescription of artificial sequenceprimer
1tagaattcat ggcgatggat gtcacaag 28227DNAArtificialDescription of
artificial sequenceprimer 2atctcgagtc actggcccag catacag 27
* * * * *